CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7:828 – 833
EDUCATION PRACTICE
Recurrent Gastrointestinal Bleeding After Negative Upper Endoscopy and
Colonoscopy
LAUREN B. GERSON
Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
This article has an accompanying continuing medical education activity on page 811. Learning Objectives—At the end
of this activity the learner should know the advantages and limitations of tests used to identify the source of recurrent
gastrointestinal bleeding with negative upper and lower endoscopy.
See CME exam on page 811.
Clinical Scenario
A 33-year-old man is referred for a 1-year history of
recurrent melena. He denies any associated weight loss or ab-
dominal pain. There is no history of aspirin or NSAID usage.
His medical history is notable for myasthenia gravis and ob-
structive sleep apnea.
The patient was hospitalized on 5 occasions with recurrent
bleeding and required 28 units of blood transfusions during
the past year for hematocrit levels less than 25%. Diagnostic
evaluation includes 2 upper endoscopic examinations and 2
colonoscopic examinations that are normal. A tagged red blood
cell scan during an episode of melena is inconclusive, suggest-
ing a possible bleeding source in the right lower quadrant.
On physical examination, the patient is in a wheelchair as a
sequela of myasthenia gravis. There is no evidence of vascular
lesions in the oral cavity, on the chest, abdomen, or the extrem-
ities. No signs of chronic liver disease are present. The remain-
der of the physical examination is normal. Laboratory exami-
nation reveals the presence of a persistent anemia, with
hemoglobin values ranging between 10 and 12 gm/dL when the
patient is not actively bleeding. A metabolic panel is normal.
There is no evidence of coagulopathy. What is the most likely
source for the patient’s ongoing bleeding? What should be the
next step in the diagnostic evaluation of this young patient?
The Problem
Obscure bleeding, defined as persistent hemorrhage
from the gastrointestinal (GI) tract without a source localized
on upper or lower endoscopic examination, is the presenting
problem in this young patient. Obscure bleeding can be further
categorized as overt in the presence of melena or hematochezia
or occult in the presence of ongoing iron deficiency anemia
with or without guaiac-positive stools.
GI hemorrhage can occur from sources located in the upper,
middle, and lower GI tracts. Approximately 5% of patients
presenting with GI bleeding will have a responsible source
located in the small intestine. Obscure GI bleeding most com-
monly originates in the small bowel, distal to the ligament of
Treitz (or papilla of Vater) and proximal to the ileocecal valve.
However, cohort studies of patients undergoing double-balloon
enteroscopy (DBE) for obscure GI bleeding have demonstrated
responsible sources within the reach of a conventional endo-
scope or colonoscope in more than 20% of cases. Upper endos-
copy should be repeated, particularly if an adequate view of the
gastric fundus was not able to be obtained on a prior exami-
nation. Lesions most commonly missed on colonoscopy include
colonic polyps and neoplasms, angioectasias, and diverticular
disease. Repeat colonoscopy should be considered in the setting
of a poor colonic preparation or in the setting of recurrent
hematochezia.
Causes of obscure bleeding are illustrated in Table 1 and
include angiodysplastic lesions (AVMs), ulcerations, other vascular
causes including Dieulafoy’s lesions, and neoplasms. On the basis
of series of patients undergoing DBE for obscure bleeding, AVMs
are more likely to be detected in patients from Western coun-
tries, whereas ulcerations (drug-induced or idiopathic), and/or
small bowel neoplasms (adenocarcinoma or lymphoma) are
more commonly detected in series reported from Asia. The
reason for this geographic variation of findings is currently
unknown.
Causes of obscure bleeding have been found to differ, de-
pending on the age of presentation (Table 1). Patients younger
than 40 years of age are more likely to present with obscure
bleeding from small bowel tumors, Meckel’s diverticula,
Crohn’s disease, or other vascular lesions. Nonsteroidal anti-
inflammatory enteropathy and angiodysplasia can be encoun-
tered more frequently in patients older than the age of 40.
AVMs have been found to be more common in elderly patients
with cardiac, vascular, pulmonary, and/or renal disease. Utili-
zation of antiplatelet or anticoagulant therapy can cause or
exacerbate bleeding from small bowel lesions, and discontinu-
Abbreviations used in this paper: AVM, angiodysplastic lesion; CE,
capsule endoscopy; CT, computed tomography; CTE, computed tomog-
raphy enterography; DBE, double-balloon enteroscopy; GI, gastrointes-
tinal; SBE, single-balloon enteroscopy; SBFT, small bowel follow-
through barium x-rays.
© 2009 by the AGA Institute
1542-3565/09/$36.00
doi:10.1016/j.cgh.2009.03.010
August 2009
Table 1. Etiology of Obscure GI Bleeding
UGI and LGI bleeding overlooked MGI bleeding
UGI lesions Younger than 40 years of age
Cameron’s erosions Tumors
Fundic varices Meckel’s diverticulum
Peptic ulcer Dieulafoy’s lesion
Angioectasia Crohn’s disease
Dieulafoy’s lesion Celiac disease
Gastric antral vascular ectasia
LGI lesions Older than 40 years of age
Angioectasia Angioectasia
Neoplasms NSAID enteropathy
Celiac disease
Uncommon
Hemobilia
Hemosuccus pancreaticus
Aortoenteric fistula
UGI, upper gastrointestinal tract; MGI, middle gastrointestinal tract;
LGI, lower gastrointestinal tract.
Reprinted with permission from Raju G, Gerson LB, Das A, Lewis B.
American Gastroenterological Association (AGA) Institute technical re-
view on obscure gastrointestinal bleeding. Gastroenterology 2007;133:
1697–1717.
ation should be considered if possible. In patients with ongoing
bleeding or anemia, the costs associated with ongoing transfu-
sions and associated hospitalizations can be significant.
Whereas patients with small bowel neoplasms can be ex-
pected to experience ongoing obscure bleeding, the natural
history of hemorrhage from vascular lesions is less well-under-
stood. Spontaneous cessation of bleeding from small bowel
AVMs has been described to occur in approximately 30%– 40%
of patients per year on the basis of information from clinical
trials comparing hormonal therapy with placebo.
Options available for small bowel imaging include small bowel
follow-through barium x-rays (SBFT), video capsule endoscopy
(CE), push and/or deep enteroscopy, and a variety of imaging
modalities including nuclear scans, angiography, computed to-
mography enterography (CTE), or magnetic imaging enterogra-
phy. With the introduction of deep enteroscopy (including DBE,
single-balloon enteroscopy [SBE], and spiral enteroscopy), intra-
operative enteroscopy has become reserved for rare patients with
ongoing hemorrhage who have not had a source identified on
prior imaging modalities, or if deep enteroscopy cannot be per-
formed without intraoperative lysis of adhesions.
Management Strategies and Supporting
Evidence
Radiologic Testing Modalities
Small bowel follow-through barium x-rays. The
diagnostic yield of SBFT in patients with obscure bleeding is
low, ranging from 0%–20%. A 2005 meta-analysis demonstrated
superiority of CE over SBFT for patients with obscure bleeding,
with a number needed to treat of three. SBFT examinations are
unable to detect AVMs, small ulcerations, or other inflamma-
tory and neoplastic disorders in a majority of cases. The major
reason to obtain an SBFT study is to exclude the possibility of
small bowel obstruction, intussusception, or stricturing associ-
ated with neoplastic or inflammatory bowel disease that might
OBSCURE BLEEDING 829
lead to retention of a subsequent capsule endoscope. However,
given its superior diagnostic accuracy, CTE has largely replaced
SBFT and should be considered the test of choice before CE in
patients with suspected obstruction.
Nuclear medicine scans. Technetium-99m–labeled
scanning can be considered in the evaluation of patients with
obscure bleeding. The sensitivity of scintigraphy is greater com-
pared with angiography as a result of the ability to detect
bleeding sites at a lower rate of hemorrhage. Diagnostic yields
for scintigraphy depend on the rate and volume of bleeding.
99mTc-labeled sulfur colloid scanning can detect bleeding rates
of 0.05– 0.12 mL/min if bleeding occurs within 5–10 minutes
after injection of the agent. With the usage of 99mTc-labeled
red blood cell scanning, hemorrhage in the GI tract can be
visualized if bleeding occurs at 0.04 – 0.1 mL/min, particularly if
5–10 mL of blood pools at a bleeding site. Nuclear scanning can
be considered when patients in a hospitalized setting experience
ongoing melena or hematochezia after a normal upper and
lower endoscopic examination but have decreased sensitivity
and specificity for detection of obscure bleeding sources com-
pared with CE. The utilization of scintigraphic screening before
angiography has been demonstrated to increase the subsequent
diagnostic yield of angiography.
Angiography. Although the overall diagnostic yield
of angiography in patients with obscure bleeding is low, rang-
ing between 5% and 15%, detection rates can be higher when
patients are actively bleeding. Prior studies have suggested that
active bleeding can only be detected if the rate of bleeding is in
excess of 1 mL/min. Modern digital subtraction angiography
can detect rates as low as 0.5 mL/min. Angiography must be
considered when there is ongoing hemorrhage after negative CE
or deep enteroscopy examinations. Positive vascular findings on
angiography can be successfully treated with embolization ther-
apy. Angiographic therapy remains an option for actively bleed-
ing ulcerations or vascular lesions, most commonly located in
the gastric fundus or duodenum, that are unable to be con-
trolled after attempts at endoscopic hemostasis. Transjugular
intrahepatic portosystemic shunts can be effective in the man-
agement of uncontrolled bleeding from ectopic varices. Al-
though the detection rate of angiography for AVMs is much
lower compared with CE, it can play a role in the detection and
management of submucosal AVMs or neoplastic lesions that
are unable to be visualized endoscopically. Angiography can
also be useful in patients with ongoing diverticular bleeding,
either in the colon or small bowel, and has largely replaced
surgical therapy in centers where available.
Meckel’s scanning. A Meckel’s diverticulum is an
embryologic remnant caused by incomplete closure of the
omphalomesenteric duct, most commonly located in the distal
ileum. Ectopic gastric mucosa, which can lead to ulceration and
hemorrhage, has been estimated to be present in from 10% to
60% of cases. Presentation with GI bleeding is more common in
children compared with adults.
Because 99mTc pertechnetate is actively secreted by the mu-
cous cells found within gastric mucosa, scintigraphic imaging is
able to detect ectopic gastric mucosa in Meckel’s diverticula.
Although scintigraphic imaging is considered to be the most
accurate noninvasive test for diagnosis, diagnostic accuracy can
range between 50% and 90%. Reasons for false-positive results can
include other inflammatory disorders, small bowel tumors, small
bowel obstruction, and AVMs. The usage of H2-blockers before
830 LAUREN B. GERSON
scanning has been demonstrated to enhance the sensitivity of
scintigraphy via the reduction of intraluminal secretions.
Computed tomography enterography. The rela-
tively new addition of CTE has enhanced the diagnostic yield in
patients with obscure bleeding. Compared with imaging ob-
tained by using standard computed tomography (CT) scanning,
CTE differs by the administration of high volume (1800 mL) of
a neutral contrast agent that can distend the bowel wall. CTE
has been shown to be useful in patients with Crohn’s disease to
distinguish between acute and chronic inflammatory changes.
Although CE has a higher diagnostic yield overall, particularly
for AVMs, CTE can be useful to exclude small bowel strictures
before CE examination and in the detection of small bowel
neoplastic, vascular, and inflammatory disorders, particularly
with submucosal involvement. The higher yield associated with
CTE has rendered it the preferred imaging test compared with
small bowel series.
Endoscopic Modalities
Push enteroscopy. Push enteroscopy can be per-
formed by using pediatric colonoscopies or dedicated 220- to
250-cm push enteroscopes to enter the proximal jejunum in
patients with obscure bleeding. There is evidence that utiliza-
tion of an overtube during the examination might be associated
with greater insertion depths, but typically the expected depth
of insertion ranges from 50 to 150 cm distal to the ligament of
Treitz. In an animal model study in which radiopaque beads
were sewn into the small intestine, push enteroscopy demon-
strated greater sensitivity compared with CE for detection of
beads in the proximal small bowel, although the overall yield
was inferior to CE. Push enteroscopy would also be expected to
be superior in the detection of pathology involving the periam-
pullary region. Approximately 15%–20% of patients with small
bowel AVMs would be expected to have such lesions within
reach of a push enteroscope.
Capsule endoscopy. The introduction of CE into
the US market in around 2000 enabled small bowel visualiza-
tion to be performed in a painless, noninvasive, and effective
fashion. Numerous studies have demonstrated the superiority
of CE compared with push enteroscopy in the diagnosis of
obscure bleeding, with an increased yield ranging between 25%
and 50%. A recent meta-analysis examining 14 trials comparing
CE with push enteroscopy for obscure bleeding demonstrated a
63% yield for CE compared with 28% for push enteroscopy. In
a pooled analysis of raw data from manufacturer-sponsored
trials, CE was shown to be superior to push enteroscopy, small
bowel series, and colonoscopy with ileoscopy. In this series, CE
identified pathology in approximately 70% of the 530 pooled
examinations.
In patients with obscure overt or occult bleeding and nega-
tive CE studies, the risk of rebleeding has been estimated to be
low. It is important to highlight the difference between a
normal or negative CE exam and a study demonstrating bleed-
ing from an unknown source. A negative CE examination refers
to a complete small bowel examination in which the capsule
enters the cecum, and no findings are demonstrated. The latter
refers to an examination in which blood is visualized in the
small bowel during the study, but no pathology is identified.
Visualization of blood during a CE examination implies that
the responsible source could be an AVM, other vascular lesion,
actively bleeding ulceration, or submucosal lesion. In this clin-
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 8
ical setting or if the patient has ongoing occult or iron defi-
ciency anemia, further investigation should occur because the
recurrence rate for bleeding is high. In one prospective study,
approximately 5% of patients with initial normal small bowel
CE examinations manifested with recurrent bleeding during a
year of follow-up. In contrast, more than 50% of patients with
AVMs on CE or bleeding from an unknown source continued
to bleed during the subsequent 12 months.
The diagnostic capability of CE can be limited by the field of
view of the capsule and by capsule reader factors, including
frame rates used during reading. Miss rates associated with an
initial CE have been described to range between 20% and 30%.
Repeat studies have been shown to be associated with higher
diagnostic yields and can be considered after an initial negative
examination, particularly in the setting of a poor mucosal
preparation.
Deep enteroscopy. Deep enteroscopy can be defined
as the usage of an enteroscope to examine small bowel distal to
the ligament of Treitz or proximal to the distal ileum. Options
for deep enteroscopy include DBE, SBE, and spiral enteroscopy.
DBE and SBE can be performed via the anterograde and retro-
grade approaches, allowing for complete examination of the
small bowel. The anal approach has not been validated for
spiral enteroscopy.
Deep enteroscopy allows the endoscopist to visualize small
bowel while providing diagnostic and therapeutic maneuvers
including tissue biopsy, cauterization and other endoscopic
therapy of bleeding lesions, polypectomy, stricture dilation, and
stent placement. Although studies have demonstrated similar
diagnostic yields of CE compared with DBE in patients with
obscure bleeding, CE might be the preferred initial diagnostic
test to determine the location of small bowel lesions because it
remains less invasive and can visualize the small bowel mucosa
within one examination. Total enteroscopy performed with either
DBE or SBE requires anterograde and retrograde approaches on
different days if visualization of the entire small bowel mucosa is
needed. Deep enteroscopy has been associated with a higher com-
plication rate (approximately 1%) compared with standard endo-
scopic procedures, particularly in patients with altered surgical
anatomy. Perforation can occur in association with polypectomy
of small-bowel polyps, stricture dilation, and in patients with
inflammatory bowel disease.
Intraoperative enteroscopy. The yield of intraoper-
ative enteroscopy has been shown to be equivalent to CE, with
a higher sensitivity compared with the other imaging modali-
ties. The ability to telescope the entire bowel is offset by in-
creased risks of morbidity and mortality. Despite the utilization
of intraoperative enteroscopy, bleeding has been reported to
recur in 12% to 60% of patients postoperatively. The major
reasons for recurrent bleeding include missed lesions as a result
of limited visibility, the evanescent nature of ectasias, and re-
currence of small bowel AVMs. Intraoperative enteroscopy
should be reserved for patients failing other diagnostic modal-
ities or in patients in whom lysis of adhesions is required to
perform deep enteroscopy.
Areas of Uncertainty
Capsule Endoscopy
The current generation of small bowel capsule endo-
scopes has a field of view of 156 degrees, an increase from the
August 2009 OBSCURE BLEEDING 831

initial capsule with 140-degree field of view. It is unclear Deep Enteroscopy

whether this increased field of view results in an increase in
diagnostic findings. Areas that remain poorly visualized on CE
include the cardia and fundus of the stomach and second
portion of duodenum, including the ampullary region. Future
capsules with potentially greater field of view and capability of
maneuvering might decrease miss rates. Studies have shown an
increased diagnostic yield when CE is repeated in the setting of
ongoing anemia or bleeding.
The decision to proceed with deep enteroscopy after CE
examination should be individualized. Because almost half of
patients with AVMs on CE examinations will stop bleeding spon-
taneously, a conservative approach could be recommended, par-
ticularly if the patient is elderly and at high risk for sedation. There
is a growing body of literature suggesting that resolution of iron
deficiency anemia can occur in a majority of patients (excluding
those with small bowel tumors) after CE examination, regard-
less of whether the patient undergoes a subsequent therapeutic
procedure.
In the setting of ongoing overt hemorrhage and/or transfusion-
dependent anemia, deep enteroscopy with endoscopic manage-
ment should be performed for patients with AVMs or other
vascular lesions on CE. Studies have demonstrated higher re-
bleeding rates for these patients. Other risk factors for rebleed-
ing have included age ⬎60 and the presence of anticoagulant
medication. For patients with ulcerative or neoplastic lesions in
the small bowel, biopsies can be obtained during deep enteros-
copy to direct further medical or surgical therapy.
The management of patients with negative capsule studies
remains less clear. Several studies have demonstrated that a
negative capsule study is associated with a low risk for rebleed-
ing during a period of 1 year, and therefore, conservative man-
agement might be appropriate in these patients. It is currently
not known whether the diagnostic yield would be greater by
using deep enteroscopy or CTE in patients with an initial
negative capsule examination and ongoing overt bleeding or
persistent iron deficiency anemia.
For patients with obscure GI bleeding, it is recom-
mended to perform deep enteroscopy initially from one ap-
proach, with tattooing the distal extent of examination, fol-
lowed by enteroscopy from the opposite approach. In the US
and Europe, most lesions, particularly AVMs, appear to be
located within the reach of an anterograde approach. Therefore,
the decision to proceed with retrograde enteroscopy after a
normal anterograde procedure compared with other imaging
modalities deserves further study. In patients with negative CE
studies and ongoing bleeding, the best next approach has not
been determined. Deep enteroscopy via the anterograde ap-
proach is a reasonable choice in patients at higher risk for
AVMs. In other patients, CTE might be a logical next step to
exclude the possibility of submucosal lesions.
Outcomes After Endoscopic Therapy
The majority of AVMs detected during CE or deep en-
teroscopy are not actively bleeding. It is not always clear whether
these lesions are causal, particularly if there are multiple lesions
throughout the GI tract. Although endoscopic therapy can be
performed, it is not clear whether these lesions would stop bleed-
ing spontaneously. It has not been established whether endoscopic
therapy is associated with higher rates of bleeding cessation com-
pared with conservative therapy for vascular lesions.
Published Guidelines
The guidelines from the 2007 AGA Institute medical po-
sition statement on obscure bleeding are shown in Figure 1. CE is
recommended as the third diagnostic test after a negative upper
and lower endoscopy. In patients with suspected bleeding from the
upper digestive tract, a second look upper endoscopy can be
considered. When massive bleeding occurs, an angiographic study
should be considered before CE. If the CE is positive, then appro-
priate therapy can occur including surgery, deep enteroscopy, or

Figure 1. Guidelines for manage-

ment of obscure bleeding. IOE, intra-
operative enteroscopy, MRE, mag-
netic resonance enteroscopy; PE,
push enteroscopy. Adapted from
Pennazio M, Eisen G, Goldfarb N.
ICCE consensus for obscure gastro-
intestinal bleeding. Endoscopy 2005;
37:1046 –1050, with permission from
Georg Thieme Verlag KG.
832 LAUREN B. GERSON
other procedures. In the setting of a negative CE, conservative
management is recommended if there is cessation of bleeding.
If bleeding recurs, then patients can undergo further testing
with repeat CE, deep enteroscopy, or imaging studies as deter-
mined by the treating physician. CTE and magnetic resonance
enterography are not listed in the current guidelines, but they
were added for patients with negative capsule examinations and
ongoing overt or occult GI hemorrhage.
Recommendations
The recommendations for this patient included CE fol-
lowed by directed intervention. The capsule study was reported to
be normal at an outside institution and was not sent for formal
review to the consulting gastroenterologist. Given the ongoing
overt hemorrhage, the capsule study could be repeated, because
increased diagnostic yields have been demonstrated on repeat
examination, particularly if patients are evaluated within 15 days
of an acute bleeding episode. In addition, miss rates have been
reported in series of patients with small bowel tumors. In a retro-
spective study of 18 patients with small bowel tumors, CE identi-
fied the tumor in 5 (33%) of the patients. In 7 (44%) of the cases,
fresh blood was identified without an associated lesion.
Because of ongoing bleeding, a DBE was performed via the
anterograde approach, demonstrating no abnormalities. DBE
was subsequently performed via the retrograde approach, re-
vealing blood clots approximately 200 cm proximal to the
ileocecal valve. No bleeding source was found after lavage of the
blood clots. In the setting of ongoing hematochezia, the patient
underwent subsequent superior mesenteric angiogram, demon-
strating a well-circumscribed hypervascular mass lesion in the
right lower quadrant. The lesion was fed primarily by branches
off the ileocolic artery and showed early venous drainage. The
differential diagnosis included benign versus malignant small
bowel tumor or vascular malformation (Figure 2). Subsequent
CT scan demonstrated a hypervascular mass arising from the
Figure 2. Image from mesenteric angiogram demonstrating hypervas-
cular mass lesion in the right lower quadrant.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 8
distal ileum consistent with a submucosal lesion, most likely a
GI stromal tumor or leiomyoma. The patient underwent resec-
tion of the involved segment of ileum, revealing a GI stromal
tumor. Two years after surgery, the patient remains asymptom-
atic without further episodes of rebleeding.
On the basis of the above discussion and summary of the
literature, a modified Figure 1 is shown for patients with a
negative capsule examination and ongoing or recurrent hemor-
rhage. Imaging with CTE or magnetic resonance enteroscopy is
added to the list of subsequent testing options for this subset of
patients and should be considered as the next testing option
after a negative CE study.
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Reprint requests
Address requests for reprints to: Lauren B. Gerson, MD, MSc, A149,
Division of Gastroenterology and Hepatology, 300 Pasteur Drive, Stan-
ford, California 94305-5202. e-mail: lgerson@stanford.edu; fax: (650)
723-8305.
Conflicts of interest
The author discloses the following: Dr Gerson has received speaking
honorarium from Given Imaging Inc. She has received grant support
and speaking honorarium from Fujinon, Inc.