1. science
2. medicine
3. surgery

Vo l u m e 8
Issue 2
Ye a r 2 0 0 9
VHJOE Editor:
John Deutsch, MD
St. Mary’s Duluth Clinic
International Editor:
Manoop S. Bhutani, MD
MD Anderson Cancer
Center, Houston TX
Above: View of Interactive Atlas, showing selected anatomical structures (left) and
corresponding oblique section (right).
The Visible Human Journal of Endoscopy (VHJOE)
is a PEER REVIEWED journal, featuring EMBEDDED
VIDEO CLIPS and IMAGE-RICH articles. VHJOE publishes
EXPERT REVIEWS from leading gastroenterologists as well
as interesting CASE REPORTS. Additionally, VHJOE features
the VISIBLE HUMAN INTERACTIVE ATLAS, a powerful,
web-based application, developed by the Center for Human
Simulation, which provides unparalleled views of human
anatomy.
Visit us online at www. vhjoe.org
Editorial Board:
William R. Brugge, MD
Massachusetts General
Hospital
Peter R. McNally, DO
Denver, CO
Thomas J. Savides, MD
University of California,
San Diego
C. Mel Wilcox, MD
University of Alabama,
Birmingham
Visible Human Project® is
a registered trademark of
the U.S. National Library of
Medicine. The National Library
of Medicine is not affilated with
the publication of this journal.
Vo l u m e 8
Issue 2
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Ta b l e o f Contents
EDITORIAL
Editorial: Non Steroidal Anti Inflammatory Agents in Gastroenterology
John C. Deutsch, M.D.......................................................................................................1
ARTICLES
NSAID Induced Small Bowel Strictures Managed by Combined Operative
Endoscopy and Surgical Resection: A Case Report and 5 year Follow Up.
P. Alexander McNally, BS; Lonnie L. Imlay, MD;
Joseph Pineau, MD; Peter R. McNally, DO .................................................................2
Angioedema Presenting as Abdominal Pain With Vomiting.
Ryan M Harden, MD, MS; John C Deutsch MD;
Jay L Parker, DO.............................................................................................................6
C A P S U L E E N D O SCOPY
NSAID Enteropathy and Capsule Retention; Complication or Guide to Therapy?
Martin I. Radwin, M.D...................................................................................................9
TO P I C R E V I E W
Topic Review: Clopidogrel and PPI Competition for CYP2C19: “Heart Attack or
Heartburn?”
Peter R. McNally, DO...................................................................................................13
CASES FROM THE ARMED FORCES INSTITUTE OF PATHOLOLOGY
NSAID Ulcer
Kathryn M. Johnson, CPT, MC, USA; Angela Levy, COL, MC, USA;
Fidelina Desoto-Lapaix, MD;
Leslie H. Sobin, MD......................................................................................................15
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Vo l u m e 8
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LITERAT U R E R E V I E W
Literature Review: FDA: Early Communication about an Ongoing Safety Review
of clopidogrel bisulfate (marketed as Plavix)
Peter R. McNally, DO.....................................................................................................18
F E AT U R E D M O V I E
Featured Movie: Splenic Vein Gas : EUS Anatomy and the Visible Human
John C. Deutsch, M.D....................................................................................................22
Editor’s Column || John C. Deutsch, M.D.
Editorial: Non Steroidal Anti Inflammatory Agents in Gastroenterology
This issue of VHJOE presents an article and a commentary
regarding the potential for gastrointestinal complications
associated with chronic use of non steroidal antiinflammatory drugs (NSAIDs). The case report, by McNally,
et. al., demonstrates the utility of a combined operative
endoscopic and surgical management of NSAID induced
small intestinal stricture. In the “Capsule Endoscopy”
section of the journal, Dr. Radwin, reviews the video capsule
endoscopy findings with NSAID enteropathy and discusses
the management issues related to capsule retention. NSAID
Enteropathy and Capsule Retention; Complication or Guide
to Therapy by Martin I. Radwin discusses anatomic changes
which can be caused by these agents, as well as diagnostic
and therapeutic interventions which may be required.
These articles should help the reader in their approach
to both NSAID complications as well as a more general
approach to capsule endoscopy. For the readers enjoyment,
I have included a video of Visible Human anatomy which
corresponds to a
capsule
endoscopy
exam of the upper
intestine.
As can be gathered
from
the
article
and
commentary,
capsule
endoscopy
is a valuable tool in
assessing small bowel
injuries,
although
Video Clip 1: Visible Human model and
it is not a risk free cross sectional anatomy which corresponds
procedure. Capsule to a small bowel capsule evaluation of the
duodenum.
retention can occur
and can lead to
surgery. Patency capsules are a relatively new method to
lessen the risk, and it is important for capsule endoscopists
to be familiar with the use of these items.
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11
Vo l u m e 8
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Article || P. Alexander McNally, BS;
Lonnie L. Imlay, MD;
Joseph Pineau, MD; Peter R. McNally, DO
NSAID Induced Small Bowel Strictures Managed by Combined Operative
Endoscopy and Surgical Resection: A Case Report and 5 year Follow Up.
Keywords: NSAIDs enteropathy, small bowel strictures,
bowel obstruction, and capsule endoscopy.
Disclaimers: none
Abstract:
We report a case of a 56 year old, Caucasian female with
recurrent small intestinal obstruction caused by NSAID
induced small bowel strictures. NSAID strictures in the
small bowel were discovered by PillCam SB (Given
Imaging, Ltd Yoqneam, Israel) endoscopy. Operative
endoscopy was successful in limiting the length of small
intestine resected by endoscopic dilation of multiple small
bowel strictures and retrieving the retained SB capsule. As
of January 2009, the patient has remained symptom free for
5 years.
Case Report:
This patient presented to our emergency department twice
in the summer of 2004, with over four hours of acute onset
abdominal pain and distention. On each occasion flat and
upright abdominal films identified dilated loops of small
intestine and air fluid levels. CT scan of the abdomen with
intravenous and oral contrast was remarkable for small
bowel dilation but without obvious cause, Figure 1. The
patient had no history of prior abdominal surgery and colon
cancer screening at 50
yrs was negative. Brief
hospitalization with
narcotic
analgesia
and nasogastric bowel
decompression was
effective in resolving
symptoms. The patient
resumed her usual
activities and diet
without limitation. An
outpatient UGI small
Figure 1: CT scan of abdomen
showing dilation of small bowel loops. bowel follow through
(SBFT) examination
was scheduled, but not completed by the patient. Roughly,
three months later the patient presented to the emergency
department with similar symptoms and radiographic
findings of small bowel obstruction. Laboratory tests
2
showed iron deficiency
anemia. After brief
hospitalization
with
intravenous
fluids,
narcotic
analgesia
and
nasogastric
decompression,
the
patient returned to
baseline. Coloileoscopy
showed only a few
sigmoid
diverticuli
and upper endoscopy
showed a small hiatal
hernia and esophagitis.
Biopsies
of
the Figure 2: UGI series with dedicated
small bowel follow through. No
stomach and duodenum
identified
only obvious bowel stenosis, dilation, or
obstruction.
Helicobacter negative,
chronic gastritis. A
dedicated UGI series with SBFT was carefully conducted
and reviewed, but noted to be unremarkable, Figure 2.
The patient’s past medical history was remarkable for
seropositive rheumatoid arthritis, hyperparathyroidism, oral
herpes simplex and gastroesophageal reflux. The patient
had a past medical history of subtotal parathyroidectomy.
Medications included Prilosec (omperazole) 20 mg daily,
Plaquenil (hydroxychloroquine sulfate) 200 mg daily,
Motrin (ibuprofen) 400 mg or 800 mg twice daily for over
8 years, and periodic prednisone for flares of rheumatoid
arthritis.
After
a
careful
multidiscipline review
of all studies and
discussion with the
patient, we felt the
most likely cause of
the patient’s recurrent
symptoms
was
NSAID enteropathy
or other obstructive
etiology
that
would
necessitate
e x p l o r a t o r y
abdominal
surgery.
Figure 3: PillCam SB showing white
septae diaphragms. The diaphragms
appear white by capsule endoscopy,
because the peristaltic pressure of
the capsule pressed on them causes
capillary blanching - they are not
white when viewed endoscopically.
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We advised the patient
that capsule endoscopy
could give additional
information as to the
cause and location of
recurrent small bowel
obstruction, but there
was a high likelihood
that the capsule would
not pass or would
impact at the sight
of the small bowel
Figure 4: PillCam SB showing
pathology. The patient
circumferential white septae.
gave informed written
consent to proceed
with capsule endoscopy, with knowledge that PillCam
retention was likely. Images from the videocapsule showed
multiple white septal strictures in the small intestine,
Figures 3,4,5. Although the patient had no obstructive
symptoms, the capsule did not pass spontaneously by two
weeks.
Surgical
and
gastrointestinal
specialties
planned
for tandem operative
intervention.
After
vertical
midline
incision, the small
intestine
was
manually examined
Figure 5: PillCam SB showing final
recorded images of white septae and and confirmed the
luminal debris at the obstructing ileal presence of multiple
stricture.
jejunal
and
ileal
strictures, Figure 6.
A palpable luminal defect (video capsule) was identified
in the mid ileum. A pediatric colonoscope (Olympus PCF140L, 11.3mm Diameter, 3.2mm Channel, 168cm working
length) was passed per os. The endoscopist advanced the
colonoscope
into
the pylorus. Then
the surgeon applied
gentle pressure to the
anterolateral
aspect
of the stomach to
splint the endoscope
and facilitate passage
of the endoscope
into the jejunum.
From this point the
Figure 6: Operative image of the
serosal surface of the jejunum. Three endoscope was gently
segmental strictures are seen and the advanced per os by
tip of the endoscope lies beneath the
the endoscopist with
surgeon’s thumb.
simultaneous gentle
surgical traction and pleating of the small intestine over the
tip of the endoscope and then gently sleeved over the length
of the endoscope. As the endoscope was advanced multiple
white circumferential strictures of variable diameter were
evident in the distal
jejunum, Figures 7,8.
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When the endoscope
was advanced into
the
ileum,
three
consecutive strictures
spaced
over
1012
inches
were
encountered
that
obstructed
passage
of the colonoscope.
With hand occlusion
of the distal ileum Figure 7: Operative endoscopic image
of sequential luminal strictures.
by the surgeon, the
endoscopist distended
the lumen with air.
The circumferential
band-like nature of the
strictures was evident.
Through the scope
(TTS), graded balloon
dilation (12, 13.5,
15 mm OD and 240
cm length, CRE™
Wireguided Balloon
Dilator,
Boston
Scientific Corp) was
effective in disruption
Figure 8: Operative endoscopic
of the strictures. Mild
image of luminal stricture with
circumferential ulceration.
intraluminal bleeding
was evident and the
endoscope easily advanced to the next obstructing stricture,
where graded balloon dilatation was repeated twice more,
Figures 9A,B,C.
Ultimately
the
PillCam capsule was
identified.
Beyond
this was a much
denser
luminal
structure with luminal
narrowing of ~5 mm,
Figure 10. Graded
balloon
dilation
was attempted, but
at a 50% reduction
of
recommended
pressure for a 12 mm
CRE balloon dilation
Figure 9A: Operative endoscopic
image of CRE balloon dilation,
pre-dilation.
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3
Vo l u m e 8
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Figure 9B: Operative endoscopic
image of CRE balloon dilation,
intra-dilation.
Figure 9C: Operative endoscopic
image of CRE balloon dilation,
post-dilation.
gastrointestinal issues.
a large serosal and
mesenteric hematoma
was evident, Figure
11. Examination of
this stricture and the
remainder of the ileum
revealed a 10 cm
segment of multiple,
dense strictures and
then normal distal
ileum to the ileocecal
region. The capsule
was retrieved and
a short segment of
dense strictures in
the distal ileum was
surgically
resected.
The
patient
was
managed in the usual
post operative fashion
and
discharged
from the hospital
on a low roughage
diet. She has been
strictly
prohibited
from ingestion of any
prescribed or over
the counter NSAIDs
and aspirin. At 5
years from surgery,
this patient is well
and has experienced
no further bowel
obstruction or other
Discussion:
NSAIDs are one of the most commonly used medications
world wide, primarily
because
of
their
effectiveness as antiinflammatory
and
analgesic
agents.1,2
Although
NSAIDs
have great benefit,
significant morbidity
and even mortality
from chronic use of
NSAIDs has been
acknowledged in the
upper gastrointestinal
Figure 10: Operative endoscopic
tract. A prospective
image of tight stricture that impeded
the passage videocapsule seen in the study by the Arthritis,
foreground.
Rheumatism,
and
4
Aging
Medical
I n f o r m a t i o n
System
(ARAMIS)
determined that 13 of
every 1000 patients
with
rheumatoid
arthritis who take
an NSAID for 1
year have a serious
gastrointestinal
Figure 11: Operative image of
complication.3 Most
evolving serosal hematoma after
physicians are aware of
attempted CRE dilation of tight
stricture shown in Figure 10.
NSAID complications
in the UGI tract to
include pill esophagitis and gastroduodenal ulceration and
hemorrhage, but only recently has the medical community
become aware of the significant potential for NSAID injury
of the small intestine.4,5,6,7 Prospective evaluation with
capsule endoscopy has shown NSAID enteropathy to be
very common in both healthy subjects and arthritic patients,
with multiple small bowel erosions or ulcers discovered in
over 70% of subjects treated with NSAID vs. 10% among
control subjects.8,9
Small bowel enteropathy caused by NSAIDs has been
hypothesized to occur through disruption of the mucosal and
cellular integrity.10 NSAIDs act as lipid-soluble weak acids
that interfere with enterocyte phospholipid membranes,
uncoupling of mitochondrial phosphorylation, ultimately
loss of mucosal barrier and cyclooxygenase-mediated
compromise of villous blood flow.10,11 Small intestinal
injury from NSAIDs runs a spectrum from macroscopically
undetectable increased intestinal permeability and mild
mucosal inflammation to ulceration to diagphragmatic
strictures.4,5,12-15 Diaphragm strictures are rare but
pathognomonic of NSAID use.4,5 There are often multiple,
2-3 mm thick septae, usually in the small intestine, which
can reduce the size of the intestinal lumen to a pinhole.5,15,16
These diaphragm strictures are thin and easily missed on
enteroclysis, where they may resemble plicae circularis.5
Our case illustrates several important clinical points
concerning NSAID enteropathy and unexplained recurrent
small bowel obstruction. First, in a patient with unexplained
small intestinal obstruction on chronic NSAIDs and without
previous abdominal surgery, NSAID enteropathy should
be considered in the differential diagnosis. In this scenario,
clinicians should not be surprised when endoscopic and
radiographic testing are negative, as the obstructing
diaphragmatic septae are easily and often missed, even on
the most carefully conducted radiographic examinations.5,6
The utility of capsule endoscopy in this clinical situation is
illustrated in the case we report.
Secondly, the PillCam SB capsule (Given Imaging, Ltd
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Yoqneam, Israel) dimensions are 11 x 26 mm, and should
pass through the normal small intestine without difficulty.
However, capsule endoscopy is usually conducted to evaluate
for intrinsic pathology, such as occult gastrointestinal
bleeding, anemia or possible Crohn’s disease. The benefit
of discovery of occult small intestinal pathology, must be
weighted against the risk of capsule retention, which has
been reported to occur in 1% (investigation of obscure
GI bleeding) to ~10% (investigation of suspected Crohn’s
disease) of cases.17,18,19 Surprisingly, a retained videocapsule
rarely impacts at a site of intestinal stenosis causing complete
bowel obstruction.16,20-22 The Agile patency capsule (Given
Imaging, Yoqneam, Israel) provides a means of evaluating
luminal patency without the risk for capsule retention. The
patency capsule is constructed from a dissolvable matrix,
which is designed to disintegrate after 30 hours and pass
though strictures in tiny pieces.23 Although the Agile
patency capsule is helpful in evaluating the risk for capsule
retention, it unfortunately does not provide luminal images.
In our case, the patency capsule would have confirmed our
preoperative suspicion of small intestinal stenosis, but would
not have provided the key information on the number and
extent of the NSAID enteropathy seen in our patient. Our
preoperative suspicion of extensive NSAID enteropathy was
confirmed by capsule endoscopy and guided our decision to
proceed with tandem surgery and operative endoscopy. We
hoped that surgically assisted enteroscopy would facilitate
endoscopic positioning for TTS dilation of multiple
strictures, monitor for complications of TTS dilations and
preclude resections of long or even multiple segments of the
small intestine. Our suspicions were confirmed, we cannot
over emphasize the importance of visually monitoring the
serosal surface during TTS of tight strictures for signs of
injury that could have resulted in perforation or restenosis.
At the time of this patient’s original presentation, balloon
endoscopy was not available and not considered as an
alternative to intraoperative endoscopy. Even now, the
authors would suggest that the extensive nature of the
NSAID enteropathy disclosed by capsule endoscopy in our
report would still persuade us to proceed with a tandem
surgical/operative endoscopic approach. Our experience of
witnessing the serosal injury with dilation of tight NSAID
strictures was helpful evaluating risk for bowel perforation.
Had we followed the “rule of three,”24 for safe dilation of
strictures, multiple sessions of balloon enteroscopy and
sequentially larger TTS dilation sessions would have been
needed to achieve luminal dilation of 15 mm used in our
case. When small intestinal strictures are less numerous and
less tight, single or double balloon enteroscopy and graded
TTS dilation would be a less invasive option, shown to be
useful by others.25,26
References
inflammation in humans. Gastroenterol. 1987;93:480-9.
1. Cryer B. NSAID gastrointestinal toxicity. Current Opinion in
Gastroenterology. 2000;16:495-502.
8. Graham DY, Opekun AR, Willingham FF, et al. Visible
small intestinal mucosal injury in chronic NSAID users. Clin
Gastroenterol Hepatol. 2005;3:55-59.
2. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity
of nonsteroidal anti-inflammatory drugs. NEJM. 1999;340:18881899.
3. Singh G, Triadafilopoulus G. Epidemiology of NSAID-induced
GI complications. J Rheumatol. 1999;26:Suppl 26:18-24.
4. Fortun PJ and Hawkey CJ. Nonsteroidal Inflammatory drugs
and the small intestine. Current Opinion in Gastroenterology.
2007;23:134-141.
5. Adebayo D, Bjarnason I. Is nonsteroidal anti-inflammatory
drug (NSAID) enteropathy clinically more important than NSAID
gastropathy? Postgrad Med J. 2006;82:186-191.
6. Lang J, Price AJ Burke M, Gumpel JM, Bjarnason I. Diaphragm
disease: pathology of disease of the small intestine induced by nonsteroidal anti-inflammatory drugs. J Clin Pathol. 1988;41:516526.
7. Bjarnason I, Zanelli G, Smith T, Prouse P, Williams P, et
al. Nonsteroidal anti-inflammatory drug-induced intestinal
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Lastly, the technique of tandem surgery and operative
endoscopy is an advanced surgical procedure that requires
experience, skill, patience and cooperative planning.27,28,29
Our center has conducted a number of tandem procedures
and suspect that disciplines of Surgery and Gastroenterology
will continue to work more closely with NOTES, Rendezvous Laparoscopic cholecystectomy and ERCP, and
therapeutic operative endoscopy.
9. Gomez-Rodriguez B, Cauendo-Alvarez A, Romero-Vasquez J, et
al. NSAIDs erosive enteropathy assessed by capsule endoscopy: a
prospective controlled trial. Gastroenterol. 2004;126:A96.
10. Bjarnason I, Takeuchi K, Simpson R. NSAIDs: the Emperor’s
new dogma? Gut 2003;52:1376-1378.
11. Kelly DA, Piasecki C, Anthony A, et al. Focal reduction of
villous blood flow in early indomethacin enteropathy: a dynamic
vascular study in the rat. Gut. 1998;42:366-373.
12. Gargot D, d’Alteroche L, Desbazeille F, et al. Nonsteroidal
anti-inflammatory drug-induced colonic strictures: two cases and
literature review. Am J Gastroenterol 1995;90:2035-2038.
13. Morris AJ, MacKenzie JF. Small bowel enteroscopy in
undiagnosed gastrointestinal blood loss. Gut. 1992;33:887-889.
14. Maiden L, Thjodleifsson B, Theodors A. A quantative analysis
of NSAID-induced small bowel pathology by capsule enteroscopy.
Gastroenterology. 2005;128:1172-1178.
Visit us online at www. vhjoe.org
5
Vo l u m e 8
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15. Goldstein JL. Videocapsule endoscopy to prospectively assess
small bowel injury with celecoxib, naproxen plus omperazole, and
placebo. Clin Gastroenterol Hepatol. 2005;3:133-141.
16. Cheifetz AS and Lewis BS. Capsule endoscopy retention: Is it a
complication? J Clin Gastroenterol. 2006;40:688-691.
17. Barkin JS, Friedman S. Wireless capsule endoscopy requiring
surgical intervention. The world’s experience. Am J Gastroenterol.
2002;97:A-83.
18. Pennazio M, Santucci R, Rondonotti E, et al. Outcome of
patients with obscure gastrointestinal bleeding after capsule
endoscopy: report of 100 consecutive cases. Gastroenterology.
2004;60:643-653.
19. Mow WS, Lo SK, Targan SR, et al. Initial experience with
wireless capsule endoscopy in the diagnosis and management of
Inflammatory Bowel Disease. Clin Gastroenterol Hep. 2004;2:3140.
20. Rondonotti E, Herrerias JM, Pennazio M, et al. Complications,
limitations, and failures of capsule endoscopy: a review of 733
cases. Gastrointest Endosc. 2005;62:712-716.
21. Delvaux M, Ben Soussan E, Laurent V, et al. Clinical
evaluation of the M2A patency capsule system before a capsule
endoscopy procedure in patients with suspected intestinal stenosis.
Endoscopy. 2005;37:801-807.
22. Cave D, Legani P, deFrachis R, et al. ICCE consensus for
capsule retention. Endoscopy. 2005 ; 62 :712-716.
Article || Ryan M Harden, MD, MS;
23. Herrerias JM, Leighton JA, Costamanga G et al. Agile patency
system eliminates risk of capsule retention in patients with known
intestinal strictures who undergo capsule endoscopy. Gastroint
Endosc 2008;67: 902-909.
24. Boyce HW. Dilation of difficult benign esophageal strictures.
Am J Gastroenterol. 2005;100:744-5.
25. Upchurch BR, Vargo JJ. Small bowel enteroscopy. Rev
Gastroenterol Disord. 2008;8:169-77.
26. Aktas H, Mensink PB. Therapeutic balloon-assisted
enteroscopy. Dig Dis. 2008;26:309-13.
27. Hammaker B and McNally PR. Utility of Emergent Endoscopy
to Guide Laparoscopy in A Patient with Acute Cholecystitis
and Unusual Laparoscopic Findings. http://www.vhjoe.org/
Volume5Issue1/5-1-3.htm
28. Wilhelm D, von Delius S, Burian M, Schneider A, Frimberger
E, Meining A, Feussner H. Simultaneous use of laparoscopy and
endoscopy for minimally invasive resection of gastric subepithelial
masses - analysis of 93 interventions. World J Surg. 2008
Jun;32:1021-8.
29. Wilhelm D, von Delius S, Weber L, Meining A, Schneider
A, Friess H, Schmid RM, Frimberger E, Feussner H. Combined
laparoscopic-endoscopic resections of colorectal polyps: 10-year
experience and follow-up. Surg Endosc. 2009 Jan 24. [Epub
ahead of print]
John C Deutsch MD;
Jay L Parker, DO
Angioedema Presenting as Abdominal Pain With Vomiting.
Disclaimer: none. The authors reported no conflicts of
interest regarding this report.
clinical presentations including life threatening hypotension
and airway obstruction. The case presented demonstrates
a classic presentation of angioedema of the small bowel
suggested by history, CT, EGD and confirmed with C1
esterase inhibitor assay.
Introduction:
Methods for Image Capture/Processing: Endoscopic
Hereditary Angioneurotic edema (Angioedema) is a
rare autosomal dominant condition in which there is a
deficiency of functional C1 inhibitor(1) which leads to
episodic interstitial fluid accumulation in the skin, larynx
or gastrointestinal tract or other region leading to various
Case Report
Keywords: Angioneurotic Edema. Angioedema.
6
images were captured from endoscopy photographic images
(Olympus) and digitized using Minolta Dimage A1 camera.
This 21 year male presented to the emergency department in
December of 2008 with a 12 hour history of cramping, mid-
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epigastric abdominal
pain and vomiting.
He denied having
this
pain
before
and had no recent
illnesses or illicit drug
use. His pain was
not associated with
eating. His emesis was
bilious and without
Figure 1: CT scan showing distended
hematemesis. He also
stomach.
denied constipation,
diarrhea,
melena,
hematochezia urinary symptoms, pruritis, rash, fever and
weight changes.
CT scan in the emergency department suggested acute
gastric outlet obstruction, as well as free abdominal fluid
and bowel edema. (Figures 1-5)
His symptoms started
improving
after
receiving
dilaudid,
ondansetron and IV
fluids in the emergency
department.
Figure 2: CT scan showing swelling near
pylorus. The admitting diagnosis was
“gastric outlet obstruction”.
His
past
medical
history was otherwise
unremarkable
and
included depression,
illicit
drug
use
with
drug-induced
psychosis,
and
insomnia.
Current medications included venlafaxine, olanzapine and
zolpidem with no recent changes. He had no allergies.
His family history was significant in that both his mother and
grandfather had angioedema. His father had a myocardial
infarction in his 40’s.
Figure 3: CT showing free intraabdominal
fluid.
His physical exam
included
stable,
normal vital signs.
Patient appeared wellhydrated,
healthy
and in no distress.
He had no swelling
or
hoarseness.
Cardiorespiratory
exam was normal.
Abdomen was soft,
without
masses,
rebound or guarding
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though he did have
some moderate midepigastric tenderness
to palpation.
Laboratory analysis
revealed an elevated
white blood count of
14.7 with 93% PMNs,
CBC was otherwise
normal. His BMP
was remarkable for
a minimally elevated
bicarbonate
level
of 30, BUN of 29,
otherwise
normal.
His lipase was 15 and
ionized calcium was
4.1.
Figure 4: CT showing edema in distal
duodenum and proximal jejunum.
An
upper
gastrointestinal
endoscopy
with
biopsy was performed
after
obtaining Figure 5: Coronal CT showing edema in
informed
consent
distal duodenum.
for the procedure.
The EGD (Figures
6,7) revealed marked edema through the distal duodenum
but without ulcerations or pathologic features. Biopsies of
the jejunum revealed normal villus architecture with mild
nonspecific chronic inflammation. The proximal duodenum
was relatively normal. Gastric biopsy revealed chronic
inflammation and numerous surface bacteria consistent with
Helicobacter pylori infection.
Based on the rapid
improvement
and
family history, further
laboratory
studies
were
performed
which included a
normal TTG but low
C4 level of 9 mg/
dL(normal
17-52
mg/dL), and low C1
Esterase inhibitor (C1
inh) antigen level of 5
mg/dL (normal 19-37
mg/dL). A diagnosis
of
Hereditary
Angioedema Type I
was made.
Figure 6: Endoscopic image of distal
duodenal edema.
The patient’s symptoms completely resolved and he was
discharged the day following admission. This patient was
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seen in allergy clinic
and started on danazol,
an
androgenic
steroid also known
as
17alpha-ethinyl
testosterone.
Summary
H e r e d i t a r y
Angioedema (HAE)
is
an
autonomic
dominant condition
Figure 7: Endoscopic image of relatively
which
causes
normal proximal duodenum.
recurrent non-pitting
subcutaneous
or
sub mucosal edema involving the arms, legs, hands, feet,
genitalia, trunk, face, tongue, larynx or bowel2 though
clinical symptoms may vary.1 A prodrome may be present
and attacks are occasionally associated with erythematic
marginatum which makes it difficult to distinguish from
anaphylaxis. Common triggers of these episodes include
dental work, trauma, cold, medications including ACE
Inhibitors, stress and pregnancy. Helicobacter pylori has
been reported as an aggravating factor in this condition.3
There are two types of hereditary angioedema, Type I and
Type II. Type I leads to synthesis of C1 inh, but it is not
secreted by cells. Type II leads to synthesis and secretion
of a non-functional C1 inh. More than 100 genetic
abnormalities have been identified leading to hereditary
angioedema and the prevalence is estimated at 1/50,000.4,5
References
1. Zuraw, Bruce L. Hereditary Angioedema. The New England
Journal of Medicine 2008; 359: 1027-36.
2. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema as
a cause of transient abdominal pain. J Clin Gastroenterol. 2002
Jan;34(1):57-61.
3. Visy B, Füst G, Bygum A, Bork K, Longhurst H, Bucher C,
Bouillet L, Cicardi M, Farkas H. Helicobacter pylori infection as a
triggering factor of attacks in patients with hereditary angioedema.
Helicobacter. 2007 Jun;12(3):251-7.
4. Bernstein IL. Hereditary angioedema: a current state-of-theart review, II: historical perspective of non-histamine-induced
angioedema. Ann Allergy Asthma Immunol. 2008 Jan;100(1
Suppl 2):S2-6.
5. Pappalardo E, Caccia S, Suffritti C, Tordai A, Zingale LC,
Cicardi M. Mutation screening of C1 inhibitor gene in 108
8
A similar type of condition, “familial angioedema,“ has
been labeled angioedema Type III, though this proceeds
through a different mechanism.
The C1 inhibitor protein (C1 inh) attenuates the proteolytic
manufacture of bradykinin and the loss or inactivity of this
protein leads to elevated bradykinin levels which has been
identified as a significant factor in angioedema.6
It is important the clinician understands this condition and
disease process in order to avoid unnecessary workup and
intervention. CT imaging shows edema7 which resolves
in a relatively short time interval. In general, endoscopy
with biopsy does not add specific information regarding
the diagnosis of angioedema. However, endoscopy does
allow inspection of the pharynx prior to insertion of the
endoscope into the esophagus to evaluate for unexpected
upper airway edema. Endoscopy also allows inspection for
other conditions which could lead to abnormal small bowel
imaging, such as sprue. Associated conditions, such as
helicobacter infections can also be identified.
Angioedema does not respond to typical therapies used in
treatment of anaphylaxis though direct administration of
fresh frozen plasma, epsilon-aminocaproic acid and danazol
have been used.8 Cinryze, C1-esterase inhibitor product
derived from human plasma, has recently been approved
by FDA to prevent attacks of this condition.8,9 If there are
no serious consequences of the attack (such as airway
obstruction) most patients experience a resolution of their
symptoms in 48-72 hours.
unrelated families with hereditary angioedema: functional and
structural correlates. Mol Immunol. 2008 Aug;45(13):3536-44.
6. Davis AE 3rd. The pathogenesis of hereditary angioedema.
Transfus Apher Sci. 2003 Dec;29(3):195-203.
7. Wakisaka M, Shuto M, Abe H, Tajima M, Shiroshita H, Bandoh
T, Arita T, Kobayashi M, Nakayama T, Okada F, Mori H, Uemura
N. Computed tomography of the gastrointestinal manifestation of
hereditary angioedema. Radiat Med. 2008 Dec;26(10):618-2.1.
8. Epstein TG, Bernstein JA. Current and Emerging Management
Options for Hereditary Angioedema in the US. Drugs.
2008;68(18):2561-73.
9. Lavine G. C1-Esterase Inhibitor Infusion (Cinryze) to Prevent
Hereditary Angioedema Attacks FDA approves new drug to prevent
hereditary angioedema attacks. Am J Health Syst Pharm. 2008
Nov 15;65(22):2080.
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Capsule Endoscopy || Martin I. Radwin, M.D..
NSAID Enteropathy and Capsule Retention; Complication or Guide to
Therapy?
NSAID Enteropathy
McNally et al. present an exemplary case report of stenosing
NSAID-induced damage of the small intestine involving
the cooperative use of several diagnostic and therapeutic
modalities to obtain a successful long term outcome. In
addition, this case queries a number of controversial issues
surrounding the approach to the diagnosis and management
of this heretofore under-recognized clinical disorder.
The noted magnitude of anti-inflammatory use, the high
frequency of small bowel pathology in normal volunteers1
and the relative rarity of such severe cases would suggest a
spectrum of disease with the majority of patients subclinical
and undiagnosed. Some authors have even suggested
that NSAID damage of the small intestine may be more
clinically relevant than NSAID gastropathy.2
The availability of wireless capsule endoscopy and deep
enteroscopy rapidly changed the landscape of our ability to
study the entity that we now call “NSAID enteropathy.” Prior
to these modalities and actual visualization of the effects
from these agents, surrogate information from indirect
measurements of small bowel damage, using techniques
such as permeability testing of intestinal integrity with
Cr-EDTA Indium labeled leukocyte scintigraphy and fecal
calprotectin,3 offered some insight into the epidemiology,
protein loss and inflammatory component of this entity.
Although pathologic features of NSAID damage were long
appreciated in rats,4 one of the earliest direct observational
studies of small intestinal mucosal damage in humans was
performed with a balloon-assisted enteroscope to aid in the
diagnosis of chronic blood-loss anemia.5 Subsequent use
of intraoperative, push enteroscopy, and double-balloon
enteroscopy has added to our knowledge of the pathologic
and histologic features of this disorder. Unfortunately, these
examinations are cumbersome, time-consuming, invasive
and not always readily available.
Therefore, capsule endoscopy has become the mainstay
of our diagnostic and research approach to the study of
NSAID enteropathy because of its ease of application,
patient tolerance and non-invasive nature. The information
obtained from a capsule study in this disorder far exceeds
that which could be offered by radiologic techniques.6
Unfortunately, the varied findings such as small erosions or
minor mucosal breaks to more severe stricturing diaphragms
and ulcerations may have unclear clinical implications as the
natural history of this entity is still as yet fully understood.
The specificity of “pathognomonic” diaphragm disease has
proven not as reliable as once thought. A compelling pilot
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study presented at the 2006 International Conference on
Capsule Endoscopy (ICCE) by Bjarnason et al. revealed a
20% incorrect diagnosis rate by four experienced blinded
clinicians when reviewing the studies of 18 patients with
established Crohn’s disease and 13 patients with NSAIDinduced enteropathy.7 (See video quiz below)
Capsule Retention
The risk of capsule retention in diaphragmatic disease, such
as in NSAID enteropathy or Crohn’s disease, is fairly high,
although complete obstruction is rare.8,9 Capsule retention,
as defined arbitrarily as a trapped capsule for at least 2
weeks, has been an area of significant controversy and
concern amongst capsule users. Several high risk patients
have been defined such as known Crohn’s disease, long term
NSAID use, surgical adhesive disease or radiation therapy.10
Unfortunately, radiologic techniques have demonstrated
significant inaccuracy at predicting retention after normal
exams and even in the setting of tight strictures.11,12 Some
investigators have conversely suggested that since retention
usually occurs at a site of notable pathology, surgical or
endoscopic therapy may be guided by this “complication”
to an effective and definitive resolution of the problem.13
Currently, however, most still consider small bowel
obstruction or documented stricture a contraindication to
capsule endoscopy for the fear of retention and impaction.
However, in one series, 19 cases of suspected small bowel
obstruction underwent capsule endoscopy with only 4
retentions, none of which caused an acute, high grade small
bowel obstruction requiring surgical remediation. These
authors concluded that capsule endoscopy can be safely
used to identify the etiology and site of a small bowel
obstruction.13
Conservative practitioners, who may otherwise avoid the
use of a potentially diagnostic capsule endoscopy in high
risk patients, may presently use the Agile patency capsule
(Given Imaging, Yoqneam, Israel) to assess functional
patency of the small bowel (Figure 1). The device is an
ingestible and dissolvable capsule made of a lactose/barium
body surrounded by dissolvable plugs at each end and
containing an internal radiofrequency identification (RFID)
tag. The presence in the intestinal tract can be determined
by an external scanner or alternatively with standard
radiography. Identically sized as the capsule endoscope, the
timer plugs at each end are designed to erode after about 30
hours allowing small intestinal fluids into the capsule body
resulting in disintegration and passage if retained longer.
Initial scanning or radiography is typically performed
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between 30-36 hours
after
ingestion.
The patient is then
followed if patency
is unconfirmed by the
continued
presence
of the capsule at
first
scanning,
until it passes for
closer
examination.
Qualitative visual and
Figure 1
tactile
assessment
regarding the condition of the passed capsule body is a
critical complimentary assessment of patency which is
more important than time of passage. If softening or any
deformation of the body is observed, regardless of the travel
time through the gastrointestinal tract, patency would be
considered highly suspect and capsule endoscopy should
probably be avoided (Figure 2).
A recent international,
multicenter
study
by
Herrerias
et
al.
investigated
the
efficacy
and
safety of the Agile
patency system in
106 patients with
documented strictures
on radiography.14 After
Figure 2
ingesting the capsule,
patients were scanned or radiographed at 3 intervals: 3238 hours, 68-72 hours and finally 94-100 hours or until
the capsule was excreted and recovered by the patient.
The capsule was qualitatively examined for disintegration
regardless of time of passage. Patency was established if
either the capsule passed “intact” or if the RFID signal was
not detected by the 32-38 hour scanning or by radiography.
If patency was established, the patient underwent standard
capsule endoscopy. If patency could not be established
during the first scanning, further determinations were
performed at the subsequent intervals or until the capsule
was recovered for examination.
Of the 106 patients enrolled, 59 (56%) excreted the capsule
intact and underwent a standard capsule study, while 47
(44%) were excreted in a deformed state and were excluded.
Interestingly, 73% of the intact capsules were excreted by
60 hours after ingestion and in one patient up to 100 hours.
In 26 (44%) of the patients, the capsule was excreted intact
prior to the first scheduled scanning. The average passage
time was 40 hours. All 59 subjects with intact capsules
completed a standard PillCam study with no cases of capsule
retention. Significant findings were found in 24 (41%) of the
examinations. A total of 17 patients had adverse effects with
the Agile capsule with only 3 considered severe consisting
of pain and nausea. One of these severe cases was felt
unlikely to be related to the Agile capsule.
The authors concluded that the patency system is a safe
and useful predictive tool in high risk contraindicated
10
patients, who would otherwise not benefit from the high
yield of significant findings obtained on capsule endoscopy,
by demonstrating successful passage of a similarly sized
capsule.
Several issues are
raised by this study
in clinical practice.
The standard protocol
for use of the Agile
system
dictates
scanning close to but
not later than 30 hours
(Figure 3). If the
RFID signal is present
Figure 3
at this time, patency is
not proven. However,
it is clear from this study that passage of intact capsules may
take up to 100 hours, most often due to slow transit through
the colon. Practitioners using this system should therefore
rely more on the qualitative assessment of the passed
capsule condition than the time of passage. Otherwise,
many patients who would benefit a PillCam study may be
excluded. Patients should be strongly encouraged to retrieve
the Agile capsule for evaluation despite the potential
repulsiveness for some.
In addition, the study didn’t evaluate those with deformed
capsules as to the actual incidence of retention or obstruction
with subsequent capsule endoscopy. It is possible that many
of these patients would pass the PillCam eventually without
clinical manifestations or need for invasive intervention.
We have all experienced patients with known strictures
or high risk manifestations who pass the capsule without
any difficulty or may retain for months or longer with the
rare need for endoscopic or surgical removal. In fact, as
exemplified in the case by McNally et al., retention occurs
at a site of significant pathology and can guide an elective
approach, whether endoscopic such as balloon-assisted
enteroscopy or intraoperative combined procedures for
a therapeutic result. My experience has been complete
acceptance and consent by patients of the strong potential
for retention or even obstruction requiring surgery when
fully explained and informed. These patients are desperate
to have the exam because of the possibility of a resolution
to their often chronic debilitating symptoms. Certainly, a
retention requiring invasive intervention for a medically
remediable condition would be unfortunate.
Therefore, should we consider capsule retention in a
symptomatic patient with stricturing disease a complication
or a victory? The consequence of a procedure that can
localize pathology where other diagnostics cannot is
therapeutically desirable. The case presented by McNally
et al. would probably not have had such a successful result
if the anticipated and well informed capsule retention had
not occurred. Every case should be considered individually,
carefully assessing the probability and desirability of
capsule retention as a diagnostic tool, possibly using the
Agile system, before deciding whether to continue with a
high risk exam.
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Video Quiz
Two patients are presented here followed by their blinded corresponding capsule images for the reader to match as an
exercise in diagnostic acumen.
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Patient 1:
63 year old woman with a long standing history of osteoarthritis involving the cervical spine and hands who has been using
Ibuprofen 600mg TID for several years. In the last 2 years, she has developed intermittent melenic stools and postprandial
periumbilical cramping. Labs reveal an iron deficiency anemia and hypoalbuminemia with negative endoscopic studies for
a bleeding source.
Patient 2:
34 year old man with chronic diarrhea, abdominal bloating and colicky postprandial abdominal pain. During the last several
months, he has observed maroon stools, low grade fevers, weakness, nausea and vomiting. An EGD revealed mild gastritis
and colonoscopy was significant for mild colitis in the rectosigmoid. An ASCA was positive and the CRP was elevated.
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References
1. Maiden L, Thjodleifsson B, Theodors A, et al. A quantitative
analysis of NSAID-induced small bowel pathology by capsule
endoscopy. Gastroenterology 2005;128:1172-1178.
8. Barkin JS, Friedman S. Wireless capsule endoscopy requiring
surgical intervention. The world’s experience [abstract]. Am J
Gastroenterol. 2002;97:A-83.
2. Adebayo D, Bjarnason I. Is nonsteroidal anti-inflammatory
drug (NSAID) enteropathy clinically more important than NSAID
gastropathy? Postgrad Med J. 2006;82:186-191.
9. Delvaux M, Ben Soussan E, Laurent V et al. Clinical evaluation
of the use of the M2A patency capsule system. Endoscopy 2005;37:
801-807.
3. Davies NM, Saleh JY, Skjodt NM. Detection and prevention
of NSAID-induced Enteropathy. J Pharm Pharmaceut Sci
2000;3(1):137-155.
10. Storch I, Barkin J. Contraindications to capsule endoscopy:
do any still exist? Gastrointest Endosc Clin North Am 2006;16:
329-36.
4. Kent TH, Cardelli RM, Stamler FW. Small intestinal ulcers
and intestinal flora in rats given indomethacin. Am J Pathol
1969;54:237-245.
11. Pennazio M, Santussi R, Rondonotti E et al. Outcome of patients
with obscure gastrointestinal bleeding after capsule endoscopy:
report of 100 consecutive cases. Gastroenterology 2004;126: 64353.
5. Morris AJ, Wasson LA, Mackenzie JF. Small bowel enteroscopy
in undiagnosed gastrointestinal blood loss. Gut 1992; 887-889.
6. Costamagna G, Shah SK, Riccioni ME et al. A prospective
trial comparing small bowel radiographs and video capsule
endoscopy for suspected small bowel disease. Gastroenterology
2002;123:999-1005.
7. Bjarnason I, Voderholzer W, Adler S, Thjodleifsson B, Maiden
L. NSAID-induced small bowel damage may be indistinguishable
from that of Crohn’s disease by wireless capsule enteroscopy. The
5th International Conference on Capsule Endoscopy, March
6-7, 2006. Boca Raton, Florida.
12
12. Spada C, Spera G, Riccioni M et al. A novel diagnostic tool
for detecting functional patency of the small bowel. Endoscopy
2005;37: 793-800.
13. Chiefetz AS, Lewis BS. Capsule endoscopy retention: is it a
complication? J Clin Gastroenterol 2006;40(8):688-91.
14. Herrerias JM, Leighton JA, Costamanga G et al. Agile patency
system eliminates risk of capsule retention in patients with known
intestinal strictures who undergo capsule endoscopy. Gastroint
Endosc 2008;67: 902-909.
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Topic Review || Peter R. McNally, DO, FACP, FACG.
Topic Review: Clopidogrel and PPI Competition for CYP2C19:
“Heart Attack or Heartburn?”
Platelet aggregation and thrombus production is the primary
mechanism of acute coronary syndrome (ACS).1 The
efficacy of clopidogrel in combination with ASA therapy
has been clearly proven to reduce recurrent coronary events
following acute myocardial infarction and the adverse
cardiovascular outcomes associated with percutaneous
cardiovascular interventions (PCI).2,3 The use of platelet
inhibitor drugs as mono or combination therapy is now
common place and has changed the management of ACS
and the “standard of care” after PCI.4,5 Unfortunately, the
improved cardiovascular survival provided by antiplatelet
therapy has been confounded by a parallel increase in
the occurrence of upper gastrointestinal events (UGIE).
In 2008, leaders of the ACCF/ACG/AHA convened and
published, “Expert Consensus Document on Reducing the
Gastrointestinal Risks of Antiplatelet Therapy and NSAID
Use.”6 These societies carefully reviewed the risks and the
potential benefit of instituting prophylactic PPI therapy to
minimizing UGIE and are outlined in Figure 1.
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Figure 2: Hepatic CYP450 Activation of Clopidogrel
Increased awareness and understanding of the need
for CYP2C19 activation of clopidogrel to effectively
prevention ACS, has prompted reconsideration of the
ACCF/ACG/AHA recommendations for the reduction of
UGIE using PPIs, which are also metabolized through the
CYP450 pathway, see Figures 3 and 4. The study by Gilard
M, et al,16 reviewed in this issue of VHJOE, highlights
the inhibitory pharmacokinetic effect of omperazole to
decrease clopidogrel CYP2C19 activation and thereby a
pharmacodynamic effect to increase platelet adhesiveness
as measured by the Platelet Reactivity Index (PRI).
Clopidogrel “poor” responders (defined as PRI >50%) were
more common in the Omperazole group 60.9% vs. 26.7% in
the placebo group (p < 0.0001).16
Deepak LB, et al. Circulation 2008; 118:1894-1909
Paralleling the observed increased risk for UGIE associated
with antiplatelet therapy, has been the unexpected observed
variance in the effectiveness of clopidogrel to prevent adverse
cardiovascular events after acute myocardial infarction and
PCI.7,8,9 Careful pharmacokinetic studies of clopidogrel
have shown that this “prodrug” requires bioactivation
through the hepatic cytochrome P450 isoenzyme pathway,
with CYP2C19 isoenzyme most important, Figure 2.13
Genetic polymorphisms among CYP2C19 isoenzyme have
identified decrease metabolic activity and direct decrease in
clopidogrel activation in select patient groups (30% whites,
40% blacks, and 55% east Asian).14,15,16
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New research data from two independent and large health
care systems have identified adverse outcomes with the use
of clopidogrel plus a PPI among patients discharged after
hospitalization with a diagnosis of ACS.17,18 Juurlink, et
al,17 conducted a large (n=13,636) population-based, nested
case control study among Canadian patients aged > 66
yrs following discharge after acute myocardial infarction
and determined that patients that experienced reinfarction
within 90 days of discharge were more likely than event-free
patients in the control group to have received concomitant
therapy with clopidogrel and PPI. They further estimated
that compared to no treatment, CYP2C19-inhibiting
PPIs were collectively associated with a 40% relative
increase in risk for recurrent myocardial infarction. Ho,
et al,18 conducted a similar large (n=8,250) retrospective
multicenter cohort study from 127 Veterans Affairs hospitals
to assess the outcomes of patients taking clopidogrel with
or without a PPI after hospitalization for acute coronary
syndrome. Death or rehospitalization for ACS occurred in
20.8% (n=615) of patients taking clopidogrel without PPI
and 29.8% (n=1,561) of patients taking clopidogrel with
PPI, adjusted odds ration (AOR), 1.25, 95% (confidence
interval, 1.11-1.41).
Results of these and other studies, have prompted the
Food and Drug Administration to launch an FDA: Early
Communication about an Ongoing Safety Review of
clopidogrel bisulfate (Plavix*) http://www.fda.gov/Cder/
drug/early_comm/clopidogrel_bisulfate.htm.19
This widespread FDA communication warns of the
potential serious drug interaction between clopidogrel
and the entire class of proton pump inhibitors (PPIs)
including PrilosecOTC, Figure 5. Confounding this class
recommendation, is the knowledge that there is significant
variance in the CYP450 metabolism of each of the PPIs
and some appear to be preferentially metabolized by nonCYP2C19 pathways, i.e., pantoprazole (CYP2C9). It will
require both pharmacokinetic and pharmacodynamic data
to show which, if any PPIs are safe to use in conjunction
with clopidogrel. Fortunately, the makers of clopidogrel
(Plavix*), Sanofi-Aventis and Bristol-Meyers Squibb are
working with the FDA to sponsor research to evaluate this
issue. Until such time that safety studies are complete,
all physicians will need to carefully evaluate the risk
benefit ratio of coadministration of clopidogrel and PPIs.
When both medications are required, selection of a PPI
metabolized through a non-CYP2C19 pathway and spacing
the administration of each medication by several hours may
be helpful since the serum half-life short (1-2 hours) for
most PPIs and competitive CYP450 interactions may be
lessened.20
References:
1. Yusuf S, Zhao F, Mehta SR, et al. Clopidogrel in unstable angina
to prevent recurrent events trial investigators. Effects of clopidogrel
in addition to aspirin in patients with acute coronary syndromes
without ST-segment elevation. N Engl J Med. 2001;345:494-502.
2. Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on
platelet reactivity in patients with stent thrombosis: results of the
CREST study. J Am Coll Cardiol. 2005;46:1827-32.
3. Bliden KP, DiChiara J, Tantry US, et al. Increased risk in patients
with high platelet aggregation receiving chronic clopidogrel
therapy undergoing percutaneous coronary intervention: Is current
antiplatelet therapy adequate? J Am Coll Cardiol.2007;49:657- 66.
4. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update
of the ACC/AHA 2004 guidelines for the management of patients
with ST-elevation myocardial infarction: a report of the American
College of Cardiology/American Heart Association Task Force on
Practice Guidelines. J AM Coll Cardiol. 2008;51:210-47.
14
5. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007
guidelines for the management of patients with unstable angina/
non-ST-elevation myocardial infarction: a report of the American
College of Cardiology/American Heart Association Task Force on
Practice Guidelines. J AM Coll Cardiol. 2007;50:e1-157.
6. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008
Expert Consensus Document on Reducing the Gastrointestinal Risks
of Antiplatelet Therapy and NSAID Use. A Report of the American
College of Cardiology Foundation Task Force on Clinical Expert
Consensus Documents. Circulation 2008;118:1894-1909.
7. Kim KA, Park PW, Hong SJ, et al. The effect of CYP2C19
polymorphism on the pharmacokinetics and pharmacodynamics
of clopidogrel: a possible mechanism for clopidogrel resistance.
Clin Pharm Ther. 2008;84:735-41.
8. Desta Z, Zhao X, Shin JG, Flockhart DA. Clinical significance
of the cytochrome P450 2C19 genetic polymorphism. Clin
Pharmacokinetic 2002;41:913-58.
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9. Mega JC, Close SC, Wivott SD, Shen L, et al. Cytochrome
P-450 Polymorphisms and Response to Clopidogrel. Engl J Med
2009;360:354-62.
action of clopidogrel associated to aspirin. J Thromb Haemost
2006; 4:2508-9.
10. Pezalla E, Day D, Pulliadath I. Initial assessment of clinical
impact of drug interaction between clopidogrel and proton pump
inhibitors. J Am Coll Cardiol. 2008;52:1038-9.
16. Gilard M et al. Influence of omeprazole on the antiplatelet
action of clopidogrel associated with aspirin: the randomized,
double-blind OCLA (Omeprazole Clopidogrel Aspirin) Study.
J Am Coll Cardiol 2008: 51:256-60.
11. Aubert RE, Epstein RS, Teagarden JR, et al. Abstract 3998:
Proton pump inhibitors effect on clopidogrel effectiveness: the
Clopidogrel Medco Outcomes Study. Circulation. 2008;118:S_815.
17. Juurlink DN, Gomes T, Ko DT, Szmitko PE, et al. A populationbased study of the drug interaction between proton pump inhibitors
and clopidogrel. CMJA. 2009;180:713-8.
12. Mega JL. Close SL, Wivott SD, et al. Cytochrome p-450
polymorphisms and response to clopidogrel. N Engl J Med.
2009;360:354-62.
18. Ho PM, Maddox TM, Wang L, Fihn SD, et al. Risk of adverse
outcomes associated with concomitant use of clopidogrel and
proton pump inhibitors following acute coronary syndrome.
JAMA. 2009;301:937-944.
13. Frere C et al, Effect of cytochrome P450 polymorphisms on
platelet reactivity after treatment with clopidogrel in acute coronary
syndrome. Am J Cardiol 2008; 101:1088-93.
14. Trenk et al. Cytochrome P450 2C19 681G polymorphism and
high on-clopidogrel platelet reactivity associated with adverse
1-year clinical outcome of elective percutaneous coronary
intervention with drug eluting or bare-metal stents. J Am Coll
Cardiol 2008; 51: 1925-34.
15. Gilard M et al. Influence of omeprazole on the antiplatelet
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19. FDA: Early Communication about an Ongoing Safety Review
of clopidogrel bisulfate (marketed as Plavix) http://www.fda.gov/
Cder/drug/early_comm/clopidogrel_bisulfate.htm
20. Li XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of
inhibitory effects of the proton pump inhibiting drugs omperazole,
esomprazole, lansoprazole, pantoprazole, and rabeprazole on
human cytochrome P450 activities. Drug Metabolism and
Disposition. 2004;32:821-827.
Cases from the Armed Forces Institute of Pathology
Kathryn M. Johnson, CPT, MC, USA; Angela Levy, COL, MC, USA;
Fidelina Desoto-Lapaix, MD; Leslie H. Sobin, MD
NSAID Ulcer
Key Words: NSAIDs, colonic ulcer.
Physical Exam:
Introduction:
On physical examination, his vital signs were within normal
limits and BMI=25.4. Right lower quadrant tenderness was
noted, but without rebound or guarding. Bowel sounds were
present. A rectal exam revealed dark brown stool.
History: A 60 year old African-American male with a history
of alcohol abuse, cocaine dependence, chronic hepatitis C
infection, degenerative joint disease, left hemicolectomy in
1994 for adenocarcinoma of the sigmoid colon and cholecystectomy in 1997 was seen prior to this presentation for
iron deficiency anemia, and then presented to the emergency
department with right lower quadrant pain and other symptoms spanning five days. He reported having watery diarrhea
for the first two days of symptoms, after eating at a vendor.
The watery diarrhea resolved, but his abdominal pain continued, with an additional symptom the day of presentation of
formed stool with specks of blood.
Laboratory Studies:
WBC=10.4 K/cmm (nml)
RBC=5.08 M/cmm (nml)
Hemoglobin=14.5 g/dL (nml)
HCT=44.5 % (nml)
MCV=87.6 cmu (nml)
RDW=22.9 % (high)
PLT=174 K/cmm (nml)
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15
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Glucose=104 mg/dl (nml)
BUN=13 mg/dl (nml)
Creatinine=0.9 mg/dl (nml)
SGOT=232 IU/L (high)
SGPT=89 U/L (high)
Alkaline Phosphatase=59 U/L (nml)
Amylase=38 U/L (nml)
Lipase=39.3 U/L (nml)
the ascending colon. Surgical resection was recommended.
Procedure:
The patient underwent a right hemicolectomy.
Gross Pathology:
Radiology Studies:
A CT scan revealed circumferential annular mural thickening
of the entire ascending colon, which resembled a longsegment apple-core like lesion.
Endoscopy Studies:
Endoscopy was performed and revealed a circumferential
lesion with ulcerated areas, consistent with colon cancer, in
Figure 1A
In the ascending colon, there was an indurated, circumscribed,
poorly delineated cobblestone like lesion located 3cm distal
to the upper lip of the ileocecal valve. This lesion measured
2.5cm. in length and 3cm. in width. The lesion was composed
of moderately broad firm rugae with multiple intervening
narrow ulcers that measured in average 1mm. The mucosa of
the broad rugae was shiny and ended in a sharp well defined
manner at the margins of the ulcers. The cut surface of this
lesion showed gross preservation of the bowel layers with
the expected small distortions caused by the ulcers.
Figure 1B
Figure 1C
Figure 1D
Axial multidetector computed tomography (MDCT) images show circumferential mural thickening of the ascending colon (arrows) with surrounding
inflammatory changes in the pericolonic fat. The luminal (mucosal) surface of the colon is irregular. The terminal ileum
(arrowhead in B) is normal.
Figure 2A
Figure 2B
Figure 2C
Coronal MDCT images show that the mural thickening of the ascending colon extends to the hepatic flexure (arrow in B). Again noted is
extensive mucosal irregularity.
16
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Histology:
The sections from a 3cm indurated area of colon described
grossly show submucosal fibrosis and crypt disarray,
consistent with healing
ulcers, as well as ulcers
that lack mucosa and
have a small amount
of associated active
inflammation. Overall,
there is a paucity of
inflammation, which
is typical in cases of
non-steroidal
antiinflammatory
drug
Figure 1: Preserved architecture with an
(NSAID)-induced
isolated crypt abscess (4x).
damage;
however,
there are scattered
crypt abscesses and
foci of cryptitis with
prominent eosinophils.
It is unclear whether
they are part of the
process or secondary to
the stenosis. There are
also areas of glandular
atypia, but these are
Figure 2: Crypt abscess with large
population of eosinophils (10x).
usually adjacent to
healing erosions, the
atypical areas are located in the regenerative zone and the
epithelium matures at the surface, indicating regenerative
atypia.
Discussion:
NSAIDs are the most commonly prescribed drugs in the
Western world, but they are not without risks. There is a
five fold increased risk of gastrointestinal hemorrhage or
perforation in women over 75 who routinely use NSAIDs,1,2
and there is a ten to
thirty fold increased
risk
of
chronic
refractory
peptic
ulcer in patients on
long term NSAID
therapy.1,3 However,
the use of lower
NSAID doses, proton
pump inhibitors and
the introduction of
Figure 3: Discrete re-epithelialized ulcer
with minimal surrounding inflammation (2x). cyclooxygenase
2
(COX-2)
specific
inhibitors have caused a decrease in serious gastrointestinal
injury due to NSAID use. Although ulceration of the
stomach and duodenum have been associated with NSAID
use for quite some time,4,5 the toxicity effects of these
drugs on the small and
large intestine have
only been investigated
relatively recently.5,6,7,8
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The
endoscopic
appearance of the
colon in a patient
using NSAIDs may be
normal, or may display
erosions, ulcers or Figure 4: Regenerative atypia in epithelium
mucosal diaphragms, lining ulcer, lamina propria and submucosal
fibrosis and closer view of crypt abscess
which are believed
with increased eosinophils (10x).
to be pathognomonic
of
NSAID-induced
injury.9,10 The luminal diameter of such mucosal diaphragms
may be as small as 1mm. Circumferential linear ulcers are
proposed to be the precursors to these mucosal diaphragms.11
To our knowledge, cases of “apple-core” lesions, such
as ours, have not yet been described in the literature. The
most common microscopic manifestation of NSAIDinduced colonic pathology is that of non-specific mucosal
ulceration, but focal colonic crypt injury, such as cryptitis or
crypt abscesses, is also
common.1
NSAIDinduced colitis may
morphologically
mimic other forms
of colitis, including
inflammatory
bowel
disease,
collagenous
colitis,
eosinophilic colitis and
pseudomembranous
Figure 5: Distinct submucosal fibrosis
colitis1;
however,
under healed ulcer (2x).
features that favor
NSAID-induced injury
include an increase in apoptotic bodies, intraepithelial
lymphocytosis (similar to lymphocytic colitis) and
unexpected tissue eosinophilia.1,12 In our case the lack of
significant lamina propria inflammation and prominence
of eosinophils within
crypt abscesses are
histologic clues to
the correct diagnosis.
The
presence
of
ulceration
in
a
background relatively
devoid of increased
inflammation
is
sometimes described
as “clean ulceration”
Figure 6: Discrete active ulcer with
and is a typical finding
only mild inflammation and partial reepithelialization (2x).
in cases of NSAIDinduced
colitis.
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17
Vo l u m e 8
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The clinical history provided by the contributor was also
supportive of the diagnosis. The patient had a three month
history of NSAID use to alleviate joint pain.
The opinions and assertions contained herein are the private
views of the authors, and are not to be construed as official,
or as reflecting the views of the Departments of the Army
and Defense.
References
1. Noffsinger A, Fenoglio-Preiser C, Maru D, Gilinsky N.
Gastrointestinal Diseases. Washington, DC: American Registry
of Pathlogy, 2007.
2. Wilcox CM, Shalek KA, Cotsonis G. Striking prevalence of
over-the-counter nonsteroidal anti-inflammatory drug use in
patients with upper gastrointestinal hemorrhage. Arch Intern
Med 1994;154:42-46.
3. Hawky CJ. Non-steroidal anti-inflammatory drug gastropathy:
causes and treatment. Scand J Gastroenterol 1996;220:124-127.
4. Silvoso G, Ivey KJ, Butt J. Incidence of gastric lesions in
patients with rheumatic disease on chronic aspirin therapy. Ann
Intern Med 1979;91:517-520
5. Odze R, Goldblum J, Crawford J. Surgical Pathology of the GI
Tract, Liver, Biliary Tract and Pancreas. Philadelphia: Saunders,
2004.
6. Allison, MC, Howatson AG, Torrance CJ, et al. Gastrointestinal
damage associated with the use of non-steroidal anti-inflammatory
drugs. N Engl J Med 1992;327:749-754.
7. Davies NM, Saleh, JY. Detection and prevention of NSAIDinduced enteropathy. J Pharm. Pharmaceut Sci 2000;3:137-155.
8. Bjarnason I, Hayllar J, MacPherson AJ, et al. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine
in humans. Gastroenterology 1993;104:1832-1847.
9. Lang J, Price AB, Levi AJ, Burke M, Gumpel JM, Bjarnason
I. Diaphragm disease: pathology of disease of the small intestine
induced by non-steroidal anti-inflammatory drugs. J Clin Pathol
1988;41:516-526.
10. Robinson MH, Wheatley T, Leach IH. Nonsteroidal antiinflammatory drug-induced colonic stricture: an unusual cause of
large bowel obstruction and perforation. Dig Dis Sci 1995;40:315319.
11.Going JJ, Canvin J, Sturrock R. Possible precursor of diaphragm
disease in the small intestine. Lancet 1993;341:638-639.
12. Lee FD. Importance of apoptosis in the histopathology of drugrelated lesions in the large intestine. J Clin Pathol 1993;46:118122.
Literature Review || Peter R. McNally, DO, FACP, FACG.
Literature Review: FDA: Early Communication about an Ongoing Safety
Review of clopidogrel bisulfate (marketed as Plavix).
Influence of omeprazole on the antiplatelet action of
clopidogrel associated with aspirin: the randomized,
double-blind OCLA (Omeprazole CLopidogrel Aspirin)
study
Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le
Calvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J.
J Am Coll Cardiol 2008;51:256-60.
Introduction:
In this edition of VHJOE, Literature in Review, we highlight
the important FDA: Early Communication about an
18
Ongoing Safety Review of clopidogrel bisulfate (marketed
as Plavix). http://www.fda.gov/Cder/drug/early_comm/
clopidogrel_bisulfate.htm
This widespread FDA communication warns of the
potential serious drug interaction between clopidogrel and
proton pump inhibitors (PPIs). Both of these medicines are
“prodrugs” requiring hepatic metabolism for activation.
Unfortunately, each medicine is metabolized through the
same hepatic CYP450 pathway, and competitive inhibition
by each leads to decreased activation for both. We have
chosen the article by Gilard, et al, to review, because
it offers an objective, readily available, and validated
measurement (Platelet Reactivity Index, PRI) of this drug
interaction and the significant increased risk of Acute
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Coronary Syndrome for persons simultaneously prescribed
clopidogrel and omeprazole. The article by Gilard, et al,
specifically examines the effect of omeprazole on the effect
of clopidogrel on PRI, but can be extrapolated to evaluation
of the effect of all available PPIs on the platelet inhibitor
effects of clopidogrel.
Aim
PowerPoint:
In a prospective, randomized double-blind study, Gilard, et
al, evaluated the impact of OMP 20mg/day vs. placebo on
clopidogrel effect by measuring platelet phosphorylationVASP as expressed as PRI.
Platelet activation & aggregation play an important role in
the pathogenesis of arterial thrombosis and can lead to acute
coronary syndrome (ACS) associated with percutaneous
coronary intervention (PCI).
Clopidogrel (Plavix*) a thienopyridine, inhibits platelet
activation induced by adenosine diphosphate (ADP).
Clopidogrel metabolites form an inactive disulfide bond
with the platelet P2Y12 ADP receptor, inhibiting platelet
reactivity.
Clopidogrel is a prodrug, needing hepatic metabolism to
acquire platelet anti-aggregation properties.
Vasodilator-Stimulated Phosphoprotein Phosphorylation
(VASP) provides an functional index of platelet reactivity to
clopidogrel.
The authors sought to test the hypothesis that OMP reduces
the biological action of clopidogrel (platelet reactivity index
or PRI) , probably due to competitive inhibition of the
CYP2C19 pathway.
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Study Design:
Prospective, blinded, placebo controlled, randomized trial
Consecutive patients undergoing elective coronary stent
implantation were considered for inclusion
All patients gave written informed consent
Controlled Treatment (all patients received)
- Aspirin 75 mg/day
- Clopidogrel 300 mg loading, followed by 75 mg/day
Randomization Treatment
- Omperazole 20 mg or Placebo
- Treatment daily for 7 days
The higher the platelet reactivity index (PRI) the more
frequently thrombosis occurs with clopidogrel treatment.
Randomized
N = 140
The hepatic CYP450 isoenzyme CYP2C19 is the dominant
enymatic pathway of prodrug (clopidogrel) activation.
Omeprazole (OMP) is a racemic compound commonly used
to suppress gastric acid production in the treatment of peptic
ulcer disease and Gastroesophageal Reflux Disease (GERD).
OMP is a prodrug, predominantly metabolized by hepatic
CYP450 isoenzyme CYP2C19.
Competitive inhibition of the CYP2C19 metabolic pathway
by OMP may decrease Clopidogrel activation thereby
decreasing PRI values and increasing risk for ACS.
N = 70
Omeprazole
N = 70
Placebo
Evaluable n = 64
(drop outs, 6)
Evaluable n = 60
(drop outs, 9)
Total Assessed for Eligibility, N=354
Study Design: Study Population:
Exclusion Criteria
- Previous treatment with Clopidogrel
- Previous treatment with PPI
- History of thrombocytopenia < 150K
- Bleeding disorder
- Liver disease
- Peptic ulcer disease
- Pregnancy
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19
Study Design: Study Evaluations
Study Results: Platelet Reactivity Index (PRI)
Conducted on Day 1 (pre-Clopidogrel) and 7 days after
(clopidogrel + OMP vs. placebo)
Platelet Reactivity Evaluation
- Vasodilator-Stimulated Phosphoprotein (VASP) BiodisStago, Asnieres, France.
- Platelet mean fluorescence intensity (MFI)
- Platelet Reactivity Index (PRI)
Platelet Reactivity Index (PRI) calculation:
100
90
80
70
60
50
40
30
20
10
0
% PRI = (MFI[PGE1] - MF1[PGE1+ADP] X 100
MFI (PGE1)
Established Criteria for Clopidogrel response:
Good
% PRI < 50%
Poor
% PRI > 50%
Study Results: Demographics
Placebo
N=60
Omeprazole
N=64
P-value
63
62
ns
♂ Gender
75%
81%
ns
Smoker
71%
64%
ns
HTN
47%
53%
ns
FHx CAD
43%
34%
ns
DM
18%
9%
ns
BMI
27
27
ns
71%
66%
ns
Age
Dyslipidemia
Omp D1 Plac D1 Omp D7 Plac D7
0
-10
-20
-30
-40
-50
-60
-70
P < 0.0001
Placebo
Omp
Study Results: Summary
Baseline demographic characteristics between the Omp and
placebo treated groups were statistically similar, Table 1.
Day 1, mean PRI was similar in both groups (83.9% vs.
83.2%), but PRI on Day 7 was significantly higher in the
Omp group (51.4% vs.. 39.8%), (p< 0.0001) Figure 1.
Clopidogrel “poor” responders (defined as PRI >50%) were
more common in the Omp group 60.9% vs. 26.7% in the
placebo group (p < 0.0001).
Table 1
20
P < 0.0001
Study Results: Variation of PRI
PRI Variation (%)
P = NS
PRI (%)
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Placebo
N=60
Omeprazole
N=64
P-value
Previous MI
8%
11%
ns
Beta-blocker
91%
83%
ns
Ace Inhibitor
50%
48%
ns
Atorvastatin
68%
67%
ns
Other statin
28%
23%
ns
The odds ratio of being a clopidogrel “poor” responder when
treated with Omp was 4.31 (95% CI 2.0 to 9.2).
Conclusions:
Omp significantly decreased the effect of clopidogrel on
platelet activation as tested by VASP phosphorylation.
Clinical implications of this study suggest that 1/3 of patients
on clopidogrel alone are unprotected against ACS (PRI >
50%) and that patients co-treated with Omp have double the
risk of ACS (60.9% have PRI > 50%).
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The empiric prescription of Omp to prevent the potential
of gastrointestinal bleeding caused by aspirin-clopidogrel
antiplatelet therapy should be stopped. Risk stratification for
GI complications should guide Omp use in these patients.
Reviewer Comments
Gilard, et al, do not answer the following questions?
Although all of the PPIs are prodrugs with some metabolism
through the CYP450. Each PPI has unique CYP450
metabolic pathways. This study does not determine if all
PPIs convey the same negative effect on clopidogrel (PRI >
50%) as shown with Omp.
PPI
with important negative clinical implication for the
coadministration of omp and clopidogrel among patients at
risk for ACS.
This study design should be applied in a similar fashion to
evaluate the effect of other PPIs on clopidogrel and the ACS
risk measured by PRI > 50%.
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For now, we should all use restraint in the prescription of
PPI among patients on clopidogrel and follow the current
recommendation of the FDA until further studies are
available.
Primary Pathway (Secondary pathway)
Omperazole
CYP2C19
(CYP3A4)
Esomperazole
CYP3A4
(CYP2C19)
Lansoprazole
CYP3A4
(CYP2C19,CYP1A)
Dexlansoprazole
CYP2C19
(CYP3A4)
Rabeprazole CYP2C19 + CYP3A4
Pantoprazole
CYP2C9
(CYP2C19 Æ sulfate
conjugation)
The investigators did not evaluate for CYP2C19
polymorphisms or other confounding variables that may have
influenced clopidogrel hepatic metabolism and explained
high PRI (>50%) seen in 30% of the placebo group.
Dr. Gilard and colleagues are commended for using a
readily available clinical assay (VASP phosphorylation) to
demonstrate the effects of Omp on clopidogrel inhibition of
the ACS marker, PRI.
The study is well designed, the results striking and
References:
1. Frere C et al, Effect of cytochrome P450 polymorphisms
on platelet reactivity after treatment with clopidogrel in acute
coronary syndrome. Am J Cardiol 2008; 101:1088-93.
2. Trenk et al. Cytochrome P450 2C19 681G A polymorphism and
high on-clopidogrel platelet reactivity associated with adverse
1-year clinical outcome of elective percutaneous coronary
intervention with drug eluting or bare-metal stents. J Am Coll
Cardiol 2008; 51: 1925-34.
3. Gilard M et al. Influence of omeprazole on the antiplatelet action
of clopidogrel associated with aspirin: the randomized, double-
The identification of increased risk for Acute Coronary
Syndrome when at risk cardiac patients receiving clopidogrel
are concomitantly given PPIs has lead to the Food & Drug
Administration to issue the following warning:
“Healthcare providers should continue to prescribe and
patients should continue to take clopidogrel as directed,
because clopidogrel has demonstrated benefits in preventing
blood clots that could lead to a heart attack or stroke.”
“Healthcare providers should re-evaluate the need for starting
or continuing treatment with a PPI, including Prilosec OTC,
in patients taking clopidogrel.”
“Patients taking clopidogrel should consult with their
healthcare provider if they are currently taking or considering
taking PPI, including Prilosec OTC.”
blind OCLA (Omeprazole Clopidogrel Aspirin) Study. J Am Coll
Cardiol 2008: 51:256-60.
4. Gilard M et al. Influence of omeprazole on the antiplatelet action
of clopidogrel associated to aspirin. J Thromb Haemost 2006;
4:2508-9.
5. Small DS et al. Effects of the proton pump inhibitor lansoprazole
on the pharmacokinetics and pharmacodynamics of prasugrel and
clopidogrel. J Clin Pharmacol 2008; 48: 475-484.
6. Siller-Matula JM et al. Effects of pantoprazole and esomeprazole
on platelet inhibition by clopidogrel. Am Heart J 2009;
157:148e1-148.e5
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21
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Featured Movie || John C. Deutsch, M.D.
Featured Movie: Splenic Vein Gas : EUS Anatomy and the Visible
Human
The featured movie
for this issue shows
an example of how
digital anatomy can
help explain pathologic
conditions. A47 yr old
patient with a history of
cirrhosis from hepatitis
C and alcohol was
found to have weight
loss and abdominal
Figure 1: Visible Human model
pain. A CT scan was
showing the splenic vein, portal vein
and proximal superior mesenteric vein. read which suggested
possible splenic
The left adrenal and spleen are added. a
The aorta is shown and an arrow
infarct and there was
identifies the celiac artery.
a
question
raised
regarding splenic vein
thrombosis. EUS was performed to further evaluate the CT
findings.
The video shows
the CT images of
note and a model
(Figure 1) of some
relevant anatomy
with the spleen,
splenic vein, left
adrenal and celiac
artery. A cross
Figure 2: Visible Human cross
section from the sectional anatomy that approximates
the subsequent EUS images.
Visible
Human
(Figure 2) shows
images similar to what would be found during radial array
EUS. The EUS images show hyperechoic material traveling
from right to left, as would be expected in flow from the
splenic vein towards the portal vein.
We hope this video demonstrates how digital anatomy and
the Visible Human can be used to help familiarize readers
with anatomic relations in this important abdominal region.
Video Clip 1: Shows the CT images
of note and a model of some relevant
anatomy with the spleen, splenic vein,
left adrenal and celiac artery.
22
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