Digestive Endoscopy 2020; 32: 204–218
13554
Review
Management of obscure gastrointestinal bleeding:
Comparison of guidelines between Japan and other
countries
Naoki Ohmiya
Department of Gastroenterology, Fujita Health University School of Medicine, Aichi, Japan
Small-bowel bleeding accounts for the majority of obscure
gastrointestinal bleeding, but it is caused by various types of
small bowel disease, upper gastrointestinal disease, and
colorectal disease. For the diagnosis, history taking and
physical examination are required, leading to a determination
of what diseases are involved. Next, cross-sectional imaging,
such as computed tomography, should be carried out, followed
by the latest enteroscopy such as small bowel capsule
endoscopy and deep enteroscopy according to the severity
of hemorrhage and patient condition. After a comprehensive
INTRODUCTION
O BSCURE GASTROINTESTINAL BLEEDING
(OGIB) has been designated as bleeding of unknown
origin that persists or recurs after a negative initial or
primary endoscopy (colonoscopy and upper endoscopy)
result.1 OGIB comprises approximately 5% of patients
presenting with all gastrointestinal (GI) hemorrhage.2 Given
recent advances in small bowel imaging with small bowel
capsule endoscopy (SBCE),3 device-assisted deep entero-
scopy including double-balloon endoscopy (DBE),4 and
radiographic imaging, the origins of bleeding deep within
the small bowel can now be identified in 41–75% of patients
with OGIB.5 Bleeding in the remaining patients can be
detected in the upper or lower GI tract at repeat esopha-
gogastroduodenoscopy or colonoscopy or there may ulti-
mately be no bleeding sources identified. Therefore, the
American College of Gastroenterology (ACG) proposed that
the term small bowel bleeding (SBB) be used when a source
of bleeding has been identified in the small bowel and that
the term OGIB be reserved for patients in whom the source
cannot be identified anywhere in the GI tract even with the
Corresponding: Naoki Ohmiya, Department of Gastroenterology,
Fujita Health University School of Medicine, 1-98 Kutsukake-cho,
Toyoake, Aichi 470-1192, Japan. Email: nohmiya@med.nagoya-
u.ac.jp
Received 31 July 2019; accepted 3 October 2019.
204
doi: 10.1111/den.
diagnosis, medical, enteroscopic, or surgical treatment
should be selected. This article reviews recent advances in
the endoscopic diagnosis of obscure gastrointestinal bleed-
ing and compares perspectives of the management of
obscure gastrointestinal bleeding in Japan with that in other
countries.
Key words: deep enteroscopy, double-balloon enteroscopy,
obscure gastrointestinal bleeding, small bowel bleeding, small
bowel capsule endoscopy
latest small bowel imaging modalities.6 In this review, the
term OGIB is used as the traditional definition.
Several guidelines to manage patients with OGIB have
already been published from various societies. This article
reviews recent advances in the diagnosis of OGIB and
compares perspectives of the management of OGIB in Japan
with that in other countries.
DIAGNOSIS
History and physical examination
T HE 2017 JAPANESE Clinical Practice Guideline for
Enteroscopy proposes that the cause and site of
bleeding in the small bowel can be estimated by asking
patients about the following: (i) presence of hematemesis;
(ii) color, consistency, and frequency of stool; (iii) abdom-
inal symptoms; (iv) presence of epistaxis; (v) past medical
history, comorbidities, or medications; and (vi) family
history.7
Hematemesis is a reliable clue to a source of bleeding
above the ligament of Treitz. Ohmiya et al.8 described that
tarry stools were mostly of upper GI, jejunal, or ileal origins,
whereas bright or dark red stools were often of ileal or
colorectal origins. Although acute massive bleeding in the
upper GI tract or bleeding of jejunal lesions causes reddish
bloody stools, and a small volume of bleeding in ileal or
colonic lesions causes black stools, especially in constipated
patients, the color and properties of the stool are often
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Digestive Endoscopy 2020; 32: 204–218
considered helpful in predicting the locations of lesions.9
Complicated abdominal pain or distention suggests small-
intestinal invagination or stenosis as a result of tumors or
inflammation, such as Crohn’s disease and intestinal tuber-
culosis. Severe abdominal pain accompanied by skin rash
with small red spots on the lower legs suggests immunoglob-
ulin (Ig)A vasculitis/Henoch-Sch€ onlein purpura.10
Age of onset and taking a detailed medical history,
including information on comorbidities, is essential for
determining SBB origin. Charlson Comorbidity Index (CCI)
is one of the most widely used comorbidity measures,11 but
little is known about the relationship between the CCI and
SBB.12 The ATRIA score has been used to estimate major
bleeding risk in patients with atrial fibrillation receiving
anticoagulant therapy.13 Ohmiya et al. developed a weighted
index (the Ohmiya index, Table 1) based on various
significant comorbidities including the CCI and ATRIA
index parameters that identified patients who developed
small bowel vascular diseases and recurrent bleeding with a
higher area under the receiver operating characteristic
(ROC) curve than the CCI or ATRIA score.14 As the
Ohmiya index increased, the ratio of small bowel vascular
disease to nonvascular disease increased; the ratio with
index <2 was <30%, but the ratio with index ≥2 was higher
than 50% (Fig. 1). When combining the age of bleeding
Table 1 Ohmiya comorbidity index: Weighted index of comor-
bidity
Assigned weight Condition
for disease
1 Angina pectoris
1 Arrhythmia
1 Diabetes mellitus
1 Congestive heart failure
1 Chronic kidney disease without
hemodialysis or peritoneal dialysis
2 Chronic kidney disease with hemodialysis
or peritoneal dialysis
2 Peripheral vascular disease
2 Valvular heart disease
3 Portal hypertensive disease
3 Hereditary vascular disease such as
hereditary hemorrhagic telangiectasia
Assigned weights for each patient’s condition. The total equals the
score.
Example: chronic kidney disease (1) with hemodialysis (2), and
portal hypertensive disease (3) = total score (6).
Chronic kidney disease: estimated glomerular filtration rate <60 mL/
min/1.73 m2.
Arrhythmia includes atrial fibrillation, paroxysmal atrial fibrillation,
sick sinus syndrome, and supraventricular tachycardia.
Management of OGIB 205
onset and the Ohmiya index, common small bowel hemor-
rhagic diseases were clearly stratified, as shown in Table 2.14
Vascular diseases represented by angiodysplasia (angioec-
tasia/angiectasia) comprise ectatic blood vessels made of
these walls with or without an endothelial lining. Small
arteriovenous communications are often present as a result
of incompetence of the precapillary sphincter. These
comorbidities listed in Table 1 may be associated with local
hypoperfusion, which may stimulate sympathetic nerves,
followed by intestinal vascular smooth muscle relaxation to
increase blood flow and reverse the hypoxia, and eventually
arteriovenous communication occurs through the ectasia.15
The American Gastroenterological Association (AGA)
Institute technical review on OGIB in 2007 proposed causes
of OGIB stratified by location, age of onset, and incidence
(Table 3).5 In comparison with other ethnic populations,
celiac disease is a specific cause in Caucasians regardless of
age. ACG clinical guidelines in 2015 proposed causes of
SBB stratified by age of onset and incidence (Table 4).6
Hereditary hemorrhagic telangiectasia (HHT, Rendu-
Osler-Weber syndrome) is one of the most well-known
hereditary entities associated with OGIB.16 It is an autoso-
mal dominant disease with high penetrance caused by
mutations in the endoglin (HHT1) and ALK1 genes (HHT2),
and its prevalence is estimated to be 1/16,500 in the State of
Vermont, USA, 1/6400 in Fyn, Denmark,17,18 and 1/8000 in
Akita prefecture, Japan.19 Most patients with HHT have a
history of epistaxis that tends to antedate the development of
cutaneous or visceral telangiectasias by a decade or more.
GI bleeding develops in the fourth or fifth decade of life.20
When we encounter an apparently healthy younger patient
with iron deficiency anemia of unknown origin, we should
take a history of spontaneous recurrent nosebleeds and its
Figure 1 Small bowel vascular disease ratios for the
Ohmiya comorbidity index.
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206 N. Ohmiya Digestive Endoscopy 2020; 32: 204–218

Table 2 Common small bowel bleeding diseases stratified by age and the new comorbidity index

Age (years)

<50 ≥50

n (%) n (%)

Comorbidities <2 Total 77 Total 191

(Ohmiya index)† 1 Meckel’s diverticulum 23 (30) 1 Inflammatory bowel diseases or 60 (31)
infection††
2 Crohn’s disease 18 (23) 2 Drug-induced injuries‡‡ 35 (18)
3 Other inflammatory bowel 11 (14) 3 Angiodysplasia/Dieulafoy’s lesion/AVM 31 (16)
diseases‡
4 Malignant tumors§ 10 (13) 4 Malignant tumors§§ 28 (15)
5 Benign tumors– 6 (8) 5 Benign tumors–– 15 (8)

≥2 Total 13 Total 123

1 Angiodysplasia/Dieulafoy’s 10 (77) 1 Angiodysplasia/Dieulafoy’s lesion/ 71 (58)
lesion/varix9 AVM/varix10
2 Acute mesenteric ischemia 1 (8) 2 Drug-induced injuries11 13 (11)
2 Meckel’s diverticulum 1 (8) 3 Inflammatory bowel diseases or 12 (10)
infection12
2 Juvenile polyposis 1 (8) 4 Benign tumors13 8 (7)
5 Chronic ischemic enteritis 7 (6)
5 Malignant tumors14 7 (6)
AVM, arteriovenous malformation.
†
Angina pectoris, arrhythmia, congestive heart failure, valvular heart disease, chronic kidney disease, hemodialysis, peripheral vascular
disease, portal hypertensive disease, hereditary vascular disease such as hereditary hemorrhagic telangiectasia.
‡
Chronic enteropathy associated with SLCO2A1 (CEAS: n = 4), simple ulcer/Behcet’s disease (n = 3), ulcerative colitis-associated enteritis
(n = 1), anastomotic ulcer (n = 1), ulcer associated with chronic intestinal pseudo-obstruction (n = 1), ulcer in the distal duodenum associated
with multiple endocrine neoplasia type 1 (n = 1).
§
Gastrointestinal stromal tumor (GIST: n = 5), malignant lymphoma (n = 3), carcinoma (n = 1), metastasis from lung adenocarcinoma (n = 1).
–
Peutz-Jeghers polyp (n = 3), hemangioma (n = 1), lipoma (n = 5), adenoma with familial adenomatous polyposis (n = 1).
††
Simple ulcer/Behcet’s disease (n = 18), anastomotic ulcer (n = 11), intestinal tuberculosis (n = 10), ulcer of unknown origin (n = 7), Crohn’s
disease (n = 4), amyloidosis (n = 3), cytomegalovirus-induced enteritis (n = 3), ancylostomiasis (n = 1), strongyloidiasis (n = 1), CEAS (n = 1),
blind-loop syndrome (n = 1).
‡‡
Non-aspirin nonsteroidal anti-inflammatory drug (n = 22), aspirin (n = 9), antihypertensive (n = 3), fluorouracil (n = 1).
§§
Malignant lymphoma (n = 11), GIST (n = 8), carcinoma (n = 4), metastasis (n = 3), carcinoid (n = 2).
––
Peutz-Jeghers polyp (n = 4), lipoma (n = 3), aberrant pancreas (n = 2), hemangioma (n = 2), lymphangioma (n = 2), pyogenic granuloma
(n = 1), myoma (n = 1).
9
Including hereditary hemorrhagic telangiectasia (n = 2).
10
Including hereditary hemorrhagic telangiectasia (n = 3).
11
Intestinal tuberculosis (n = 3), ulcer of unknown origin (n = 2), Crohn’s disease (n = 2), amyloidosis (n = 2), simple ulcer/Behcet’s disease
(n = 1), anastomotic ulcer (n = 1), adhesive obstruction-induced ulcer (n = 1).
12
Non-aspirin nonsteroidal anti-inflammatory drug (n = 7), aspirin (n = 5), warfarin (n = 1).
13
Lymphangioma (n = 2), adenoma (n = 2), aberrant pancreas (n = 1), hemangioma (n = 1), myoma (n = 1), inflammatory fibroid polyp (n = 1).
14
GIST (n = 3), carcinoma (n = 2), metastasis (n = 1), malignant lymphoma (n = 1).

familial aggregation and carry out a physical examination of
minute telangiectasia on the lips, nasal mucosa, tongue,
palms, and palate.
Intestinal phlebectasias are venous varicosities, without
portal hypertension, consisting of a markedly dilated
tortuous vein with a normal vascular wall and scant
connective tissue stroma. They occur primarily in elderly
men. Phlebectasias may also occur in the oral cavity, mostly
at the base of the tongue, where they are called caviar spots
or sublingual phlebectasias, and in the scrotum. These
orocutaneous signs are clues to the presence of intestinal
lesions in elderly men with GI bleeding.15 The jejunum is
the most commonly involved site.21,22
Blue rubber bleb nevus syndrome is a rare congenital
disease characterized by the development of multiple venous
malformations (formerly cavernous hemangiomas) in the
skin, GI tract, and other organs. Small bowel complications
are intussusception, volvulation, and SBB.23 The lesions can

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Digestive Endoscopy 2020; 32: 204–218 Management of OGIB 207

also cause numerous extraintestinal problems such as ortho-
pedic deformities, central nervous system involvement, spinal
cord compression, disseminated intravascular coagulation,
thrombocytopenia, hemothorax, and hemopericardium.5
Regarding acquired von Willebrand disease, Veyradier
et al.24 showed that most patients with GI bleeding
angioectasias lacked the largest multimers of von Wille-
brand factor, suggesting that its deficiency contributed to the
bleeding diathesis. von Willebrand factor is produced in the
endothelial cells, released into the bloodstream as a high
Table 3 Etiology of obscure GI bleeding in the American
Gastroenterological Association (AGA) Institute technical review
2007
molecular weight multimer that binds factor VIII and plays
an important role in hemostasis. It is cleaved by ADAMTS-
13, glycosylated and cleared from the bloodstream with a
half-life of 12–20 h.25 The mechanical forces of aortic
stenosis, left ventricular assist device, and extracorporeal
membrane oxygenation can easily shear and deform the high
molecular weight multimers into smaller fragments, which
impairs thrombosis and interferes with platelet aggrega-
tion.26,27 von Willebrand factor fragmentation may, by itself,
be pro-angiogenic and potentially involved in GI hemor-
rhage in these severe settings.26,28
Cross-sectional imaging

Upper GI and lower GI Mid GI bleeding

bleeding overlooked
Upper GI lesions
Cameron erosions
Fundic varices
Peptic ulcer
Angiectasia
Dieulafoy’s lesion
Gastric antral vascular
ectasia
Lower GI lesions
Angiectasia
Neoplasms
Cross-sectional imaging techniques for evaluation of the
small bowel include helical computed tomography enterog-
raphy/enteroclysis (CTE), helical CT angiography, and
Younger than 40 years of age magnetic resonance enterography/enteroclysis (MRE).5 In
Tumors an emergency, dynamic or enhanced helical CT without
Meckel’s diverticulum
enterography/enteroclysis provides important information
Dieulafoy’s lesion
regarding mass lesions such as tumors, inflammation, and
Crohn’s disease
Celiac disease vascular diseases, including arteriovenous malformation
Older than 40 years of age (AVM, Fig. 2) and ischemic enteritis.10 The diagnostic
yields of cross-sectional imaging for OGIB in previous
Angiectasia studies were 17–48%.29–36
NSAID enteropathy
Celiac disease
Uncommon Small bowel capsule endoscopy and patency
Hemobilia capsule
Hemosuccus pancreaticus Small bowel capsule endoscopy has been a significant
Aortoenteric fistula
breakthrough for the diagnosis of small bowel diseases.3 It

Table 4 Causes of small bowel bleeding in the American College of Gastroenterology clinical guideline 2015

Common causes Rare causes

Under age 40 years Over age 40 years

Inflammatory bowel disease Angioectasia Henoch-Scho €nlein purpura

Dieulafoy’s lesion Dieulafoy’s lesion Small bowel varices and/or portal hypertensive enteropathy
Neoplasia Neoplasia Amyloidosis
Meckel’s diverticulum NSAID ulcers Blue rubber bleb nevus syndrome
Polyposis syndromes Pseudoxanthoma elasticum
Osler-Weber-Rendu syndrome
Kaposi’s sarcoma with AIDS
Plummer-Vinson syndrome
Ehlers-Danlos syndrome
Inherited polyposis syndromes (FAP, Peutz-Jeghers)
Malignant atrophic papulosis
Hematobilia
Aorto-enteric fistula
Hemosuccus entericus
FAP, familial adenomatous polyposis; NSAID, nonsteroidal anti-inflammatory drug.

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208 N. Ohmiya
Figure 2 Arteriovenous malformation in the ileum. (A) Dynamic contrast-enhanced arterial-phase image (arrow). (B)
Angiography of the superior mesenteric artery indicates dilated artery, nidus, and early venous return. (C) Retrograde
double-balloon enteroscopy shows a reddish pulsating subepithelial lesion with telangiectasia on the surface.
acquires and transmits digital images at the rate of two per
second (PillCam SB2 (Medtronic, Minneapolis, MN,
USA), EndoCapsule (Olympus Corp., Tokyo, Japan), and
OMOM (JINSHAN Science & Technology, Chongqing Shi,
China)), three per second (MiroCam (IntroMedic, Seoul,
Korea), or 20 per second (CapsoCam (Saratoga, CA,
USA)). PillCam SB3 (Medtronic, Minneapolis, MN, USA)
has a faster adaptable frame rate system (two or six images
per second), depending on the passage speed. The “Top
100” feature that carries out automatic selection of the 100
most clinically relevant images by artificial intelligence has
been recently installed in PillCam software v9.0 (Medtronic,
Minneapolis, MN, USA), which detects 83.5% of high
bleeding potential lesions and over 95.5% of angioec-
tasias,37 suggesting that this is a promising tool to facilitate
strenuous capsule reading. The other advantage of SBCE is
its ability to indicate the nearest device-assisted enteroscopy
route. Candidate cutoff value for route selection is half of
small-bowel transit time in the complete SBCE examina-
tion,38 or 75% of the total time from ingestion to arrival at
the cecum.39 SBCE has a diagnostic yield for OGIB that
varies from 41% to 80% when compared with DBE.5 An
adverse event of SBCE is retention. Even if an OGIB patient
presents without obstructive symptoms, a capsule can
possibly lodge above various strictures, including with
suspected or documented Crohn’s disease, past medical
history of abdominal surgery or radiation therapy, patients
on NSAIDs or potassium over a long period. Small bowel
series and CT enteroclysis before SBCE are not highly
effective for predicting endoluminal narrowing.40 In these
patients, the Agile or tag-less patency capsule should be
© 2019 Japan Gastroenterological Endoscopy Society
Digestive Endoscopy 2020; 32: 204–218
carried out before SBCE.41 However, the patency capsule is
not entirely safe as it may induce small bowel obstruction
requiring surgery,41 retention of the coating membrane after
dissolution, and inaccurate prediction by plain X-ray only
leading to capsule retention. Ongoing or previous small
bowel obstruction is therefore a contraindication of the
patency capsule and SBCE. The diagnostic yields of SBCE
for OGIB in previous studies were 47–86%.14,42–48
Device-assisted deep enteroscopy
Double-balloon endoscopy has been a significant break-
through for diagnosing small bowel diseases as well as
SBCE. Furthermore, DBE has enabled endoscopic tissue
sampling and treatment.4 The success rate of total entero-
scopy varies in the literature, but in Japanese literature, the
rate is 61–86% in attempted cases.8,49 In a systematic review
involving 9047 DBE procedures, a total of 61 major
complications (perforation, pancreatitis, bleeding, and aspi-
ration pneumonia) were reported, with a pooled major
complication rate of 0.72% (95% CI, 0.56–0.90%).50 These
events may be associated with a long examination time, or
aggressive passage through the stenotic or adhesive intes-
tine. During insertional procedures in DBE, the upper GI
tract and large intestine should also be carefully examined
because OGIB lesions could possibly be located there.
When targeted lesions are inaccessible during DBE as a
result of severe adhesions, laparoscopic-assisted DBE has
reportedly been promising.51
Single-balloon enteroscopy (SBE) was introduced after
DBE. SBE involves only one balloon attached at the tip of
Digestive Endoscopy 2020; 32: 204–218 Management of OGIB 209

Figure 3 Diagnostic algorithm for obscure gastrointestinal bleeding by Japanese Clinical Practice Guideline for Enteroscopy in
2017. CT, computed tomography; IVR, interventional radiology.

Figure 4 Secondary intestinal tuberculosis. (A) Chest computed tomographic image shows consolidation with cavity in the left
lung. (B) Double-balloon enteroscopy shows circular deep ulceration in the distal ileum.

the sliding tube. Although instrument preparation time is Spiral enteroscopy originally required a spiral overtube,
faster, the complete enteroscopy rate was reported to be and its progress was advanced by a gentle push and manual
lower with SBE than with DBE, accompanied by a lower clockwise rotation inducing pleating of the small bowel on
diagnostic yield.52 the enteroscope.53,54 Motorized spiral enteroscopy

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Figure 5 Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). (A) Chest computed tomographic image shows
arteriovenous malformation in the right lung (arrow). (B) Dynamic computed tomography shows hepatic heterogeneous
enhancement and early venous return which suggests shunting. (C) Gastroscopy shows multiple bright red telangiectasias. (D)
Double-balloon enteroscopy shows multiple bright red telangiectasias in the jejunum and ileum.

(PowerSpiral; Olympus Corp., Tokyo, Japan) is a new
technology with an incorporated user-controlled motor
contained in the handle of the endoscope. This offers the
possibility to accelerate the procedure, facilitate insertion,
and simplify the technique with a single operator,55 but its
accessibility in the adhesive intestine, adverse events, and
interventional ability need to be studied further.
The diagnostic yields of deep enteroscopy for OGIB in
previous studies were 44–94%.8,10,14,56–61
Angiography
Angiography may detect both acute bleeding and nonbleed-
ing lesions (particularly AVM, which often have character-
istic angiographic features including a dilated artery, a nidus,
and early venous return, Fig. 2B).5 When active bleeding
occurs at a rate of ≥0.5 mL/min, extravasation of contrast
into the bowel lumen may be found on mesenteric
angiography.62 Transarterial embolization (TAE) is an
effective procedure for the treatment of acute GI bleeding,
but bowel infarction is the most serious complication. This
complication rate was reported in 4.3% of acute GI bleeding
patients, and it was an important factor associated with in-
hospital mortality.9,63
Nuclear scans
Role of technetium-99 m-labeled red blood cell scans or
technetium-99 m-labeled human serum albumin scans is
limited only in settings unable to undergo deep enteroscopy
or SBCE. They require a bleeding rate of 0.1–0.4 mL/min
for a positive result.64
Meckel’s scan using 99mTc-pertechnetate is used for the
evaluation of OGIB.65 Sensitivity is reported to be 75–
100%.66 The sensitivity and specificity of Meckel’s scan for
ectopic gastric mucosa were 75–94% and 97–98%, respec-
tively, in studies primarily focused on pediatric popula-
tions.67–69 In the adult population, however, Meckel’s scan

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Digestive Endoscopy 2020; 32: 204–218
Figure 6 Recommended approaches for diagnosis and treatment of obscure gastrointestinal bleeding of the 2015 European
Society of Gastrointestinal Endoscopy clinical guidelines. CTE, computed tomography enterography/enteroclysis; DAE, device-
assisted enteroscopy; VCE, videocapsule endoscopy.
was less sensitive and specific because the prevalence of
heterotopic gastric mucosa declines with age in symptomatic
Meckel’s diverticula.70 This relatively less invasive tech-
nique may be useful for ruling out Meckel’s diverticulum,
especially in children.
Diagnostic algorithm and management of
OGIB
The 2017 Japanese Clinical Practice Guideline for Entero-
scopy proposed a diagnostic algorithm and information for
the management of OGIB (Fig. 3). In patients with both
overt and occult OGIB, contrast-enhanced helical CT should
be done first in patients without contraindications such as
renal failure and previous allergy to contrast agents. If
possible, dynamic contrast-enhanced multiphase imaging
should be selected to show better enhancement of small
bowel lesions. Even in patients with contraindications, plain
CT should be carried out to show intra-abdominal pathol-
ogy. CTE is recommended to depict luminal, intramural, and
extraluminal lesions, but, in emergent cases, CTE can be
skipped. In addition to abdominal scanning, chest scanning
should be carried out simultaneously because the etiology of
OGIB is likely pulmonary disease such as tuberculosis
(Fig. 4), metastasis from lung cancer, and AVM in HHT
(Fig. 5). First-line CT examination can prevent delayed
diagnosis of malignant tumors, leading to mortality.
Management of OGIB 211
When abnormalities are detected on abdominal CT, deep
enteroscopy should be carried out by the nearest approach.
Once the bleeding source is diagnosed during deep
enteroscopy, medical, endoscopic, or surgical treatment
can be selected. Even for lesions that are indications for
surgery, endoscopic marking with tattooing and/or clipping
is useful for identification during laparoscopic surgery. In
patients with massive bleeding, angiography was reported to
be recommended before deep enteroscopy.5 TAE is strictly
indicated in patients with massive bleeding of unidentified
origin, bleeding from inaccessible sites, or endoscopically
untreatable bleeding who are reluctant to undergo surgery.
When the lesions are suspected to be indications for surgery
but are enteroscopically inaccessible, intraoperative entero-
scopy is also recommended.
When abnormalities are undetected on abdominal CT and
we cannot wait for completion of SBCE in patients with
emergent massive bleeding, we should immediately carry
out deep enteroscopy after resuscitation and blood transfu-
sion. Here, the oral approach is generally recommended
because the anal approach is difficult due to insertion
through massive bloody feces, but when the bleeding
sources are undetected, the anal approach should be
subsequently carried out.
When abnormalities are undetected on abdominal CT in
hemodynamically stable patients, SBCE is preferred. In
patients at risk for capsule retention, such as in those with
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212 N. Ohmiya Digestive Endoscopy 2020; 32: 204–218

Figure 7 Algorithm for suspected small bowel bleeding of the American College of Gastroenterology in 2015. CTE/MRE,
computed tomography enterography/enteroclysis-magnetic resonance enterography/enteroclysis; VCE, videocapsule endo-
scopy.

Figure 8 Algorithm for the diagnosis and management of obscure gastrointestinal bleeding of the American Gastroentero-
logical Association Institute technical review on obscure gastrointestinal bleeding in 2007. CE, capsule endoscopy; DBE, double-
balloon enteroscopy; IOE, intraoperative enteroscopy; PE, push enteroscopy.

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Digestive Endoscopy 2020; 32: 204–218 Management of OGIB 213

Figure 9 Approach to diagnosis and management of obscure gastrointestinal bleeding of the Korean guidelines for capsule
endoscopy in 2013. CE, capsule endoscopy; CTE, computed tomography enterography; DE, deep enteroscopy; EGD,
esophagogastroduodenoscopy; GI, gastrointestinal; IOE, intraoperative enteroscopy; PE, push enteroscopy; SB, small bowel.

suspected or documented Crohn’s disease, a previous
history of abdominal radiation therapy, and chronic NSAID
users, the Agile or tag-less patency capsule system should
be used before SBCE. Capsule retention rate is approxi-
mately 1% of OGIB patients even before the introduction of
a patency capsule; therefore, the patency system is not
always used. When abnormalities are detected but cannot be
accurately diagnosed during SBCE, further examination at
deep enteroscopy is necessary. If a diagnosis can be made
during SBCE, although dependent on the case, treatment can
be started immediately. For example, if characteristic
findings with Crohn’s disease such as longitudinal ulcera-
tion, cobblestone appearance chiefly in the ileum and
longitudinal or circumferential alignment of erosions or
linear erosions both in the jejunum and ileum are
observed,71 intensified medical treatment including biolog-
ical agents can be started.
When abnormalities are undetected by either CT or
SBCE, we should determine whether further work-up is
needed, according to the severity and frequency of OGIB,
and the duration between bleeding onset and examination.
We must note that SBCE is not a perfect diagnostic
technique because the SBCE miss rate was reported to be
18.9%, 5.9%, and 0.5% for small bowel tumors, vascular
disease, and ulcers, respectively.72 In particular, in the
duodenum and the proximal jejunum, diagnostic yield of
small bowel tumors was significantly lower than that located
in other areas because of the rapid passage of SBCE.73
Furthermore, as a result of the impossibility of air insuffla-
tion, the detection rate of diverticular disease is also low.10
The diagnostic yields of SBCE and deep enteroscopy for
OGIB become lower two or more weeks after onset in
previously overt OGIB.74,75 These lower yields may result
from the healing of small mucosal defects without apparent
scars, nonbleeding Dieulafoy’s lesion that has already
stopped bleeding and appears as normal mucosa, and
nonbleeding small angiodysplasias between numerous Ker-
ckring’s folds that are easily missed at enteroscopy.
Therefore, patients with comorbidities who are likely to
have vascular disease and develop rebleeding shortly after
bleeding, and younger patients who possibly have Meckel’s
diverticula or Crohn’s disease should be further investigated.
If further work-up is considered unnecessary, antithrom-
botics and eating should be started quickly, although this
may provoke rebleeding.76 If patients rebleed, repeat SBCE
should be done as soon as possible. When SBCE detects
bleeding outside the small intestine, esophagogastroduo-
denoscopy or colonoscopy should be carried out.

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214 N. Ohmiya Digestive Endoscopy 2020; 32: 204–218

Figure 10 Low-risk intraluminal gastrointestinal stromal tumor (GIST) in the proximal jejunum presenting with overt previous
obscure GI bleeding that was overlooked by small bowel capsule endoscopy. (A) Contrast-enhanced computed tomographic
image. Arrow indicates the jejunal tumor. (B) Double-contrast barium meal roentgenogram in the jejunum (arrow, 22-mm tumor).
(C) Chromoendoscopic image with indigocarmine of the tumor with ulceration on the surface in double-balloon enteroscopy.

Figure 11 Low-risk extraluminal gastrointestinal stromal tumor (GIST) in the distal jejunum presenting with overt previous
obscure GI bleeding that was overlooked by small bowel capsule endoscopy and even successful total double-balloon
enteroscopy and misdiagnosed as left ovarian tumor. (A) Contrast-enhanced computed tomographic image. Arrowheads
indicate an enhanced tumor. (B) Luminal side of the surgical specimen shows normal mucosa except for a 2-mm depression
(arrow). (C) Serosal side of the surgical specimen shows a 47-mm extraluminal tumor.

The diagnostic algorithm proposed in the 2017 Japanese
Clinical Practice Guideline for Enteroscopy is based on the
concept that device-assisted deep enteroscopy is the best
diagnostic modality because it enables detailed observation,
tissue sampling, and endoscopic ultrasonography with a
miniature probe. However, the procedure takes time and the
effort of a skillful endoscopist,77 and is possibly complicated
by perforation, pancreatitis, aspiration pneumonia, or
bacteremia. Therefore, SBCE and contrast-enhanced CT
should appropriately be carried out. Most cases of SBB can
be controlled medically, by enteroscopy, interventional
radiology, and surgical therapy. However, the rate of
rebleeding of vascular disease, such as angiodysplasias
and Dieulafoy’s lesions, is significant even after endoscopic
hemostasis.8,10,14,78 We should also note that in many
patients with angiodysplasias and Dieulafoy’s lesions, GI
bleeding stops spontaneously. Development of vascular
disease is associated with the various comorbidities men-
tioned previously. If these comorbidities can be treated (e.g.
renal transplantation for renal failure, valve replacement for
valvular heart disease), bleeding is unlikely to occur again.
These radical treatments, however, are not applicable to
many patients; therefore, repeated hemostasis is often
required for deep enteroscopy.
The different perspective of the diagnostic algorithm
between Japan and other countries is what should be carried
out as the first-line procedure and the concept of device-
assisted deep enteroscopy as the core modality. The 2015

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Digestive Endoscopy 2020; 32: 204–218
European Society of Gastrointestinal Endoscopy clinical
guidelines recommend SBCE as a first-line examination in
patients with both occult and overt OGIB.79 According to
this algorithm, when SBCE is negative, clinical follow up
with a “wait and see” policy is advocated; then, if OGIB
recurs, repeat SBCE, device-assisted enteroscopy, or CTE
should be selected (Fig. 6). CTE may be a complementary
examination to SBCE in selected patients with overt but not
occult OGIB when SBCE is nondiagnostic. The 2015 ACG
clinical guidelines recommend SBCE as a first-line proce-
dure for small bowel evaluation after upper and lower GI
sources have been excluded in patients with both occult and
overt OGIB who have no small bowel obstruction. When
SBCE is negative, further evaluation is warranted and may
include observation/iron supplements or repeat endoscopy,
SBCE, or Meckel’s scan/surgery  intraoperative endo-
scopy. In patients with possible small bowel obstruction,
CTE/MRE is recommended (Fig. 7).6 The AGA Institute
technical review of 2007 proposed an algorithm for the
diagnosis and management of OGIB and recommends
SBCE as a first-line procedure in patients with both occult
and overt bleeding and, when SBCE is negative, further
evaluation is warranted and may include observation/
medical treatment or repeat endoscopy, SBCE, Meckel’s
scan, or laparoscopy/intraoperative endoscopy, but CT was
not adopted. In patients with massive bleeding, angiography
is recommended (Fig. 8).5 The Korean guidelines for
capsule endoscopy of OGIB recommended SBCE as a
first-line procedure because detection rates of SBCE for the
origins of OGIB were superior to CT angiography. CTE is
recommended only in cases with SBCE contraindications or
suspicious neoplasms (Fig. 9).80
The advent of SBCE and device-assisted endoscopy has
allowed endoscopic luminal imaging of the whole small
bowel but cannot easily identify intramural and extraluminal
lesions, especially SBCE. Figure 10 shows a gastrointestinal
stromal tumor (GIST) of the intraluminal type that was
overlooked by SBCE, presumably due to impossible air
insufflation and suspected rapid passage, located in the
proximal jejunum. Figure 11 shows a GIST of the extralu-
minal type that was overlooked by both SBCE and even
successful total double-balloon enteroscopy. If there are
abnormalities detected on screening CT, SBCE is not always
needed, and device-assisted enteroscopy can be the next
examination. Therefore, the Japanese guidelines recommend
CT as the first-line examination, but this may be ascribed to
the fact that Japan has the largest number of CT scanners
available in the world (111.49 per million population),
followed by Australia (64.35), Iceland (43.68), USA
(42.64), Denmark (39.72), Switzerland (39.28), Latvia
Management of OGIB 215
(39.13), Korea (38.18), Germany (35.13), Italy (34.71),
Greece (34.22), and Austria (28.64).81
In conclusion, OGIB should be diagnosed efficiently and
promptly using CT, SBCE, and device-assisted enteroscopy
with possible bleeding causes derived from elaborate history
interview and physical examination.
ACKNOWLEDGMENT
T HE AUTHOR THANKS Dr Akira Ohashi at Nagoya
Ekisaikai Hospital for kindly providing pictures of
surgical specimens and computed tomography.
CONFLICTS OF INTEREST
A UTHOR N.O. IS an Associate Editor of Digestive
Endoscopy.
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