Introduction

Push enteroscopy studies have revealed that angiodysplasias are

the leading cause of occult or obscure bleeding fromthe small in
testine [1, 2]. Due to the limited visibility of the jejunum and
ileum, however, the extent of disease, the origin of bleeding,
and also any effect of therapy have remained uncertain in a con
siderable number of patients. Wireless capsule endoscopy,
which now allows endoscopic visualization of the entire small
intestine, has confirmed angiodysplasia to be the most impor
tant cause of bleeding from the small intestine [3, 4].
Overall, bleeding from intestinal angiodysplasias accounts for
only 3% of cases of gastrointestinal bleeding [2, 3]. However,
hemorrhage frequently recurs and is difficult to treat. In severe
cases, hundreds of blood transfusions may be required over years
[1, 5]. Single lesions may be treated endoscopically by argon plas
ma coagulation, laser or heat coagulation, or surgical resection.
However, multiple angiodysplasias disseminated over the jeju
num and ileum are frequently found, requiring extensive endo
scopic treatment or repeated surgical resections. As lesions tend
to reappear at other sites of the intestine after local therapy and
there is no established medical treatment, bleeding in these pa
tients remains a major therapeutic challenge [1, 5].
As angiodysplasias result from unregulated neoangiogenesis, in
hibition of vessel growth provides a specific approach to treating
the cause of the disease. Thalidomide has been shown to be a po
tent inhibitor of angiogenesis in experimental models [6] and
may therefore also inhibit growth of intestinal angiodysplasias.
Macroscopic appearance of intestinal angiodysplasias
under antiangiogenic treatment with thalidomide
J. Bauditz
H. Lochs
W. Voderholzer
Institution
Charit University Hospital, IVth Department of Medicine, Berlin, Germany
Corresponding author
J. Bauditz, M.D. Universittsklinikum Charit IV. Medizinische Klinik und Poliklinik Schumannstr. 20/21
10117 Berlin Germany Fax: + 4930450514923 Email: juergen.bauditz@charite.de
Submitted 23 June 2006 Accepted after revision 12 July 2006
Bibliography
Endoscopy 2006; 38 (10): 10361039 Georg Thieme Verlag KG Stuttgart New York
DOI 10.1055/s2006944829 ISSN 0013726X
Background and study aims: Angiodysplasias are the main
cause of bleeding from the small intestine. Single lesions may
be treated by endoscopic coagulation or surgical resection. How
ever, multiple disseminated angiodysplasias are frequently pres
ent, making local therapy an unfavorable choice or impossible.
Currently there is no established medical treatment available
for these patients. Thalidomide is a potent inhibitor of angiogen
esis in experimental models. As angiodysplasias are a result of
unregulated vessel growth, antiangiogenic treatment may inhib
it growth of angiodysplasias.
Patients and methods: We studied the effect of thalidomide on
the macroscopic appearance of angiodysplasias in three patients
with bleeding due to multiple angiodysplasias of the small intes
tine. During the previous 12 months patients had experienced
37 bleeding episodes and had received a mean of 16.7 blood
units. Results: After start of treatment with thalidomide at a
dose of 100 mg daily, no further bleeding episodes occurred. Al
though thalidomide was stopped after 3 months, bleeding did
not recur and hemoglobin reached and maintained normal levels
without further transfusions for the whole observation period
(mean followup 34 months). Repeat wireless capsule endoscopy
after 3 months thalidomide demonstrated substantial reduc
tions in the number, size, and color intensity of angiodysplasias.
Conclusion: Thalidomide seems to inhibit growth of intestinal
angiodysplasias and may be useful for treatment of patients
with bleeding related to angiodysplasias. Wireless capsule en
doscopy allows monitoring of the macroscopic effects of antian
giogenic therapy.
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To investigate whether the use of thalidomide results in changes
in the mucosal appearance of angiodysplasias, we treated three
patients with bleeding angiodysplasias of the small intestine
and monitored treatment by means of repeat wireless capsule
endoscopy, which has been shown to be the gold standard for di
agnosis of smallbowel lesions [7].
Patients and methods
The three patients (all men; age range 7283) had suffered from
recurrent bleeding related to multiple intestinal angiodysplasias
for 1.56 years. Multiple argon beamer treatments, and colonic
resection (in patient no. 2), had shown no lasting effect. Within
the previous 12 months the patients had experienced between
3 and 7 bleeding episodes and had received a mean of 16.7 blood
units. Before the start of thalidomide treatment, wireless capsule
endoscopy (Given Imaging, Yoqneam, Israel) demonstrated mul
tiple angiodysplasias disseminated over the jejunum and ileum
in all three patients.
Thalidomide was given at a dose of 100 mg/day for 3 months. A
clinical evaluation with monitoring of hemoglobin levels was
performed at baseline and at least every 4 weeks thereafter.
Wireless capsule endoscopy was repeated after the end of treat
ment. The wireless endoscopy findings were analyzed by blinded
investigators. Patients were followed up for a mean of 34 months
(range 2450 months). Since thalidomide can cause peripheral
neuropathy (PNP), a neurological evaluation was performed be
fore and during treatment. Electromyography was performed at
baseline, and at the end of treatment, or when clinical symptoms
possibly related to neuropathy occurred. Informed consent was
obtained from all patients.
Results
Overall, treatment was well tolerated. Apart from transient fa
tigue in all three patients and evidence of subclinical PNP found
on electromyography in patient no. 3, no sideeffects were seen.
During thalidomide therapy, the number, size and colour intensi
ty of the angiodysplasias decreased. In all three patients, hemo
globin reached normal levels without further transfusions and
remained stable during a mean followup of 34 months. No re
bleeding occurred during followup (Figures 1 and 2; Table 1).
Discussion
Bleeding from intestinal angiodysplasias is relatively rare, but it
is clinically relevant as the bleeding may become chronic and is
very difficult to treat. Although treatments with several substan
ces have been evaluated over more than 50 years, there is cur
rently no established medical treatment for patients with recur
rent bleeding related to multiple angiodysplasias of the small
bowel. Hormonal therapy initially showed promising results [5],
but these were not confirmed in a recent randomized study [8].
During recent years, insight into the pathophysiology of angio
genesis and vascular malformations has substantially improved.
Vascular endothelial growth factor (VEGF) has been identified as
a key mediator of the early phase of angiogenesis, in which prim
itive endothelial vessels are formed [9]. High local concentra
tions of VEGF result in aberrant angiogenesis with formation of
angiodysplastic lesions composed of primitive endothelial ves
sels, which lack a smooth muscle cell layer and are susceptible
to rupture [10]. Intestinal angiodysplasias in patients with recur
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,

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s
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h
1 2 3 4 5 6 7 8 9 10 20 30
Thalidomide started
month
4
3
2
1
0
Figure 2 Number of blood transfusions/month ( SEM) in three pa
tients with angiodysplasias of the small intestine. No further transfu
sions were required after thalidomide treatment was started (follow
up after start of treatment: range 2450 months, mean 34 months).
Figure 1 Typical ap
pearance of angio
dysplasias from the
small intestine of pa
tient no. 1: a before,
and b after 3 months
thalidomide treat
ment. Remaining le
sions were uniformly
smaller and paler red
in color.
Bauditz J et al. Macroscopic appearance of intestinal angiodysplasias treated with thalidomide Endoscopy 2006; 38: 10361039
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rent bleeding have been shown to strongly express VEGF along
the endothelial lining of dysplastic vessels [11], indicating a pro
liferative stage of angiogenesis. Thalidomide has recently been
identified to be a potent inhibitor of VEGFmediated angiogen
esis [6].
We therefore speculated that antiangiogenic therapy with thali
domide might inhibit growth of intestinal angiodysplasias. In a
recent case series we demonstrated that thalidomide reduced
transfusion requirements and VEGF serum levels in patients
with Crohns disease and obscure bleeding [12]. In the present
instance, we treated three separate patients with multiple angio
dysplasias of the small intestine and severe recurrent bleeding.
Monitoring by capsule endoscopy after 3 months thalidomide
treatment revealed regressive changes in the number and mac
roscopic appearance of the angiodysplasias. Before therapy, mul
tiple angiodysplasias presented with the typical appearance a of
cherryred color. Repeat capsule endoscopy after 3 months of
thalidomide treatment demonstrated a substantial decrease in
the number of angiodysplasias and also shrinkage and discolora
tion of the remaining lesions, indicating atrophy of vessel com
plexes. One might argue that capsule endoscopy cannot exactly
identify the same lesions before and after therapy. However, a
study comparing this modality with intraoperative endoscopy
has found a high sensitivity of 67% to 100% for the detection of
lesions, with angiodysplasia being the most common lesion [7].
In view of these results, and since capsule endoscopy is the only
method for the detection of smallintestinal lesions, we consider
our findings precise enough to come to the conclusion that an
giodysplasias have in fact decreased in number and shape in our
patients.
The changes in macroscopic appearance were paralleled by clin
ical signs of efficacy. Bleeding stopped in all patients after the
start of treatment. Hemoglobin levels became normal and stayed
so without further transfusions during the whole observation
period. As the number of previous bleeding episodes independ
ently predicts rebleeding in patients with gastrointestinal angio
dysplasias [11], our patients were at high risk of rebleeding. Ces
sation of bleeding by chance in all three patients therefore seems
unlikely.
Although these results have to be confirmed in larger controlled
trials, the morphological changes and clinical efficacy observed
in our patient series further support the idea that thalidomide
may be useful for treatment of bleeding related to intestinal an
giodysplasia. Consistently with our findings, a therapeutic effect
of thalidomide on intestinal bleeding has recently been reported
in a patient with acute myelogenous leukemia and angiodyspla
sias [13] and also in two patients with Oslers disease [14,15].
During recent years, inhibition of angiogenesis has evolved as a
promising approach for treatment of malignant diseases [16].
Some of the currently developed antiangiogenic substances
might not only be useful as anticancer agents but could also be
efficacious for treatment of bleeding from intestinal angiodys
plasias. In addition to clinical monitoring, wireless capsule en
doscopy presents a feasible method for evaluation of different
treatment strategies for bleeding from angiodysplasias.
In conclusion, thalidomide seems to inhibit growth of intestinal
angiodysplasias and may be useful for the treatment of patients
with bleeding related to angiodysplasia. Wireless capsule endos
copy is a valuable tool for monitoring the macroscopic effects of
new therapeutic strategies such as antiangiogenic therapy.
Competing interests: None
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In brief
Interesting small series of three patients with multiple small
intestinal angiodysplasias, treated with thalidomide, with good
clinical effect and also a probable morphologic effect seen on re
peat capsule endoscopy.
Table 1 Total number of bleeding episodes/blood transfusions and comparison of number and size of angiodysplasias and hemoglobin val
ues before thalidomide treatment, after 3 months of thalidomide treatment, and after 24 months from the start of treatment
Patient
no.
Bleeding episodes; blood transfusions Number of angiodysplasias Mean size of angiodysplasias, mm Hemoglobin, g/dl
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After 3 months
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Bauditz J et al. Macroscopic appearance of intestinal angiodysplasias treated with thalidomide Endoscopy 2006; 38: 10361039
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