Inflammatory Bowel
Disease (IBD) is a general term that applies to a number of diseases the
most prominent of which are:
A
comparison
of ulcerative colitis and Crohn's disease shows that they have many features in
common yet are clearly distinctive enough to be considered two separate
clinical disorders. The most characteristic differences are:
- ulcerative
colitis always starts in the rectum, is continuous along the large bowel, and
rarely affects the small intestine while Crohn's disease is discontinuous and,
although most common in the terminal ileum, can affect any part of the
gastrointestinal tract;
- ulcerative
colitis tends to affect only the inner layer of the colon while Crohn's disease
affects all layers of the bowel (i.e. is transmural).
Pathological
specimens available include:
The etiology of
both disorders is unknown; however, it is believed that there may be a genetic
predisposition toward their development due to their increased prevalence in
certain ethnic groups. Both diseases are more common in whites and occur about
equally in males and females. The incidence of onset is highest between the
ages of about 15 to 25 and 45 to 55 years.
Review the
pathology references provided below for more information.
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Nuclear Medicine
imaging of IBD may be performed with:
- Ga-67 citrate
(not a radiopharmaceutical of choice);
- In-111
leukocytes;
- Tc-99m
leukocytes.
Gallium (Ga-67)
citrate
Gallium (Ga-67)
is an iron analogue that avidly binds to iron-binding proteins
including:
- transferrin
which is the primary transport protein for Ga-67 within the circulatory
system;
- lactoferrin
which is stored within specific leukocyte granules and is released by the
leukocytes at sites of inflammation;
- ferritin, an
intracellular protein, which mediates uptake of iron / gallium into
bacteria;
- siderophores
which are low molecular weight compounds produced by bacteria that also mediate
uptake of iron / gallium into bacteria.
By binding to
the intracellular lactoferrin of leukocytes, gallium-67 is transported to sites
of infection where it is deposited when the leukocytes excrete some of their
lactoferrin.
Gallium is
believed to localize in inflammatory lesions by diffusing across "leaky"
capillaries into the extracellular space and binding to iron-binding proteins
that are in relatively high concentrations in inflammatory lesions. Because of
the protein binding and incorporation into bacteria, the gallium remains fixed
within the lesion as circulating levels decrease slowly over time.
During the first
24 hours about 15% to 25% of the administered dose is excreted by the kidneys.
After 24 hours the gastrointestinal system becomes the primary route of
excretion. Activity located within the gastrointestinal tract, especially the
colon, makes interpretation of abdominal images difficult. By 48 hours about
70% to 75% of the administered dose still remains in the body.
Because of it's
localization characteristics, the use of gallium (Ga-67) citrate is generally
considered more effective for chronic lesions than for acute ones. In
inflammatory bowel disease, the use of gallium tends to be limited to ruling
out the presence of abscesses. WBC (leukocyte) imaging is the method of choice
for abdominal inflammation imaging.
In-111 / Tc-99m
leukocytes
Leukocytes may
be labelled with either:
- In-111 as
oxine or tropolone,
- Tc-99m as
exametazime (HMPAO).
Both In-111 and
Tc-99m leukocytes localize in sites of inflammation and infection.
Neutrophils are
strongly attracted to acute pyogenic infectious and inflammatory conditions
which tend to dominate intra-abdominal infections and inflammatory processes.
Mononuclear leukocytes tend to dominate in more chronic and nonpyogenic
infections and inflammatory disorders.
Imaging with
In-111 or Tc-99m labelled leukocytes offers a number of significant advantages
over gallium (Ga-67) citrate and is the procedure of choice for detecting
inflammatory bowel disease. The primary reasons for this are:
- the normal
excretion of gallium through the bowel and the potential this creates for false
positive interpretation;
- poor image
resolution of gallium resulting in difficulty in interpretation;
- the 2 to 4
day period required to obtain results for gallium.
Of the two
radionuclides used to label leukocytes, Tc-99m (as Tc-99m exametazime (HMPAO))
is now generally preferred. Tc-99m is readily available and produces superior
quality images.
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Inflammatory
Bowel Disease imaging procedures are indicated for providing clinically useful
information for:
- initial
diagnosis of IBD;
-
determination of the extent and severity of IBD;
- evaluation
of the complications of IBD;
- monitoring
the success of management and treatment of IBD.
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Patient
Preparation
Prior to
injection, ensure that the patient has not had a recent barium contrast
study.
The test
procedure is explained to the patient.
Prior to the
imaging appointment, the patient undertakes a regime of bowel cleansing by
taking citrate/milk of magnesia and by self-administering an enema.
Radiopharmaceutical
Gallium-67 is
cyclotron produced and decays by electron capture with a physical half-life of
78 hours. During the decay process, it emits several gamma photons ranging in
energy from 93 keV to 880 keV. Three of the gamma energy peaks are suitable for
imaging: 93 keV (38%), 185 keV (21%) and 300 keV (17%). A medium or high energy
collimator is required.
Gallium (Ga-67)
citrate is supplied ready-to-use in multidose vials. An adult dose is about 150
to 200 MBq while pediatric doses are generally in the order of 1.5
MBq/kg.
The organ that
receives the highest dose is the large intestine.
Equipment
A LFOV,
multipeak gamma camera equipped with a medium or high energy collimator is
required. Images may be collected directly onto film or with an interfaced
computer system using a 64 x 64 or 128 x 128 matrix. The camera's analyzers are
set with 15 to 20% windows over gallium's three primary photopeaks at 93 keV
(38%), 185 keV (21%) and 300 keV (17%). A gamma energy at 394 keV (4%) also
exists and contributes to degradation of image resolution.
Alternatively, a
total body imaging system may be used with the same analyzer settings as
above.
Image / Data
Acquisition Parameters
Imaging is
generally performed 48 hours post-injection but earlier images obtained at
about 6 and/or 24 hours may enhance the diagnostic quality of the
procedure.
A protocol from
The Society of Nuclear Medicine
is available for reference.
 Procedure using In-111
/ Tc-99m Leukocytes
Patient
Preparation
When preparing
and administering In-111 / Tc-99m leukocytes, it is necessary to have
safeguards in place to ensure blood specimens are not mixed up and that the
correct labelled specimen is reinjected into the patient.
Prior to
beginning the procedure, ensure that the patient has not had a recent barium
contrast study.
The test
procedure is explained to the patient.
Radiopharmaceutical(s)
In-111
leukocytes
In-111 is
cyclotron produced and decays by electron capture. It has a physical half-life
of 67.4 hours and two imagable photopeaks at 171 keV (90.0%) and 247 keV
(94.2%). These energies require the use of a medium energy collimator which
results in lower image resolution compared to Tc-99m and a LEAP
collimator.
In-111 oxine and
In-111 tropolone are neutral, non-polar, lipophilic chelates that penetrate the
cell membrane of leukocytes. Once inside the cell, the trivalent In-111 ion
appears to dissociate from the chelate and form relatively stable bonds with
cytoplasmic and nuclear proteins. A number of differences in the two chelating
agents exist but one of the most significant is that In-111 oxine cannot be
used to label leukocytes in the presence of plasma because of the higher
affinity of In-111 for transferrin than for oxine. In-111 tropolone is a
stronger chelating agent and using it does not require the removal of plasma
prior to cell labelling. There is some evidence to suggest that labelling
leukocytes in plasma (i.e. with In-111 tropolone) may cause less stress to the
cells and result in less damage.
Both forms of
In-111 label all types of blood cells indiscriminately and so the leukocytes
must first be separated from the other cells (i.e. red cells and platelets)
prior to labelling. The result is a mixed population of labelled leukocytes
(i.e. neutrophils, monocytes and lymphocytes) which is acceptable for most
imaging procedures. Labelling efficiencies in the order of 80% to 90% can be
achieved with either agent. If the labelling efficiency is <40% the cells
should not be reinjected.
Normal
biodistribution of In-111 leukocytes demonstrates activity in the spleen,
liver, bone marrow, and transiently in the lungs.
Complete details
of the labelling procedure for In-111 leukocytes are beyond the scope of this
presentation but are available in several of the texts and journals referenced.
About 75 MBq of
In-111 oxine or tropolone is initially used in the labelling process. A dose of
about 10 to 20 MBq of In-111 leukocytes is reinjected back into an adult
patient. For pediatrics, the activity administered is about 0.25 to 0.50 MBq/kg
(minimum ~ 1.8 to 2.3 MBq; maximum ~ 20 MBq).
Tc-99m
leukocytes
Tc-99m is
obtained from a Mo-99/Tc-99m generator as pertechnetate. It has a half-life of
6.03 hours and a single gamma photopeak at 140 keV (88%).
Tc-99m
exametazime (HMPAO) is a neutral, non-polar, lipophilic radiopharmaceutical
originally developed for cerebral perfusion imaging. The compound is unstable
and breaks down over time into a hydrophilic secondary complex. In its
lipophilic form, Tc-99m exametazime is able to cross the cell membrane of
leukocytes. Once inside the cell, its structure alters to the hydrophilic form
and the Tc-99m becomes trapped within the cell. Tc-99m exametazime leukocyte
labelling can be performed in the presence of plasma and appears to have a
significant degree of selectivity for granulocytes.
Tc-99m
leukocytes localize in the spleen, liver, bone marrow, and transiently in the
lungs similar to In-111 leukocytes. Tc-99m leukocytes also show normal
localization in the bowel (after about 3 to 4 hours in adults; sooner in
pediatrics) associated with sloughing of leukocytes into lumen of GI tract. In
addition, activity is seen in the urinary tract and sometimes in the
gallbladder. These additional sites of normal distribution are due to the
excretion of the hydrophilic secondary complexes of Tc-99m exametazime. Fasting
for 2 to 4 hours prior to the study may reduce hepatobiliary excretion and
subsequent bowel activity, especially in children. Studies have indicated that
Tc-99m leukocyte imaging may be more sensitive than In-111 leukocyte imaging
for detecting and determining the extent of IBD, especially in the small
bowel.
Once again,
details of the labelling procedure may be found in the text and journal
references provided. Labelling efficiencies range between about 50% to 70%.
About 1.5 GBq of Tc-99m pertechnetate is initially used to prepare the Tc-99m
exametazime (unstabilized) and about 1.0 to 1.2 GBq of this is used to label
the leukocytes. A dose of about 200 to 500 MBq of Tc-99m leukocytes is
reinjected back into the adult patient. For pediatrics, the activity
administered is about 3.5 to 7.5 MBq/kg (minimum ~20 - 40 MBq; maximum = adult
dose).
Equipment
In-111
leukocytes
A LFOV gamma
camera equipped with a medium energy collimator and interfaced to a nuclear
medicine computer system is preferred. The camera's analyzers are set at 171
keV and 247 keV with 15% to 20% windows. The acquisition uses a 64 x 64
matrix.
Tc-99m
leukocytes
A LFOV gamma
camera equipped with a low energy collimator and interfaced to a nuclear
medicine computer is preferred. The camera's analyzer is set at 140 keV with a
15% to 20% window. The acquisition uses a 64 x 64 or 128 x 128
matrix.
Image / Data
Acquisition Parameters
In-111
leukocytes
Although for
many disorders In-111 leukocyte imaging is generally performed 18 to 24 hours
after reinjection of the labelled WBC's, imaging for IBD must be performed
within 4 hours of reinjection. Common imaging times for IBD are at 0.5 to 1.0
hour and at 2 to 3 hours after reinjection. The reason for this is that by 18
to 24 hours a significant portion of inflammed mucosal cells and leukocytes
will have shed into the intestinal lumen and been distributed distally by
intestinal peristalsis. Imaging at 18 to 24 hours may be performed at the
disgression of the Nuclear Medicine physician.
The patient is
initially positioned supine within the field of view and an anterior image of
the liver and spleen is acquired for 200k to 500k counts. Imaging times may be
as long as 10 to 15 minutes depending upon the activity administered and the
total counts acquired for the image.
Following the
first image, anterior and posterior images are acquired over the abdomen and
pelvis for the same time as the liver/spleen image.
Protocols from
The Society of Nuclear
Medicine, The
University Hospital, London, ON and
The
Crump Institute for Biological Imaging, Los Angeles, CA are available for
reference.
Tc-99m
leukocytes
Because of the
appearance of bowel activity after about 3 to 4 hours, imaging for IDB is
performed between about 30 to 60 minutes after reinjection for adults and
between about 20 to 40 minutes for pediatrics. Subsequent sequential images up
to about 4 hours may be requested by the Nuclear Medicine physician depending
on the results of each set of images.
The patient is
initially positioned supine within the field of view and an anterior image of
the liver and spleen is acquired for 750k to 1000k counts. Following the first
image, anterior and posterior images are acquired over the abdomen and pelvis
for the same time as the liver/spleen image.
Protocols from
The Society of Nuclear
Medicine, Reston, VA,
The University
Hospital, London. ON and
The
Crump Institute for Biological Imaging, Los Angeles, CA are available for
reference.
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Interpretation of
In-111 / Tc-99m Leukocyte Studies
Interpretation of
In-111 Leukocyte Studies
Normal
distribution of In-111 leukocytes at the time of imaging is in the liver,
spleen and bone marrow. Accumulation of activity in a location other than these
normal sites is suggestive of infection or inflammation.
Interpretation of
Tc-99m Leukocyte Studies
Tc-99m
leukocytes normally accumulate in the liver, spleen and bone marrow with
transient activity present in the lungs. Activity in the bone marrow produces
images that look remarkably like bone scans. The 1-hour images demonstrate lung
activity but no activity in the gastrointestinal system.
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Pathology
Texts
Stevens A, Lowe JS. Pathology. London: Times Mirror,
1995: 228 - 230
Internet
URL's
Ulcerative
Colitis hosted by The National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDKD) of the National Institutes of Health (NIH).
The Crohn's Disease,
Ulcerative Colitis, Inflammatory Bowel Disease Pages hosted by Bill
Robertson. Try the FAQs (Frequently Asked Questions).
Crohn's and Colitis
Foundation of Canada provides an excellent on-line brochure titled "The Facts About
Inflammatory Bowel Disease".
Crohn's
Disease hosted by The National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDKD) of the National Institutes of Health (NIH).
Crohn's Disease
Resource Center hosted by HealingWell.com provides information on
both Crohn's disease and Inflammatory Bowel Disease.
Procedure
Texts
Bernier DR, Christian PE, Langan JK, eds. Nuclear Medicine:
Technology and Techniques. 3rd ed. St. Louis: Mosby - Year Book, 1994: 402
- 411.
Datz FL. Handbook of Nuclear Medicine. 2nd ed. St. Louis:
Mosby - Year Book, 1993: 136 - 142, 232 - 239.
Early PJ, Sodee DB, eds. Principles and Practice of Nuclear
Medicine. 2nd ed. St. Louis: Mosby - Year Book, 1995: 702 - 713, 714 -
724.
Kipper SL. Radiolabelled Leukocyte Imaging of the
Abdomen. In: Nuclear Medicine Annual 1995. New York: Raven Press, 1995: 81
- 128.
Thrall JH, Ziessman HA. Nuclear Medicine: The Requisites.
St. Louis: Mosby - Year Book, 1995: 149 - 164.
Journals
Arndt J-W, van der Sluys A, Blok D, et al. Prospective
Comparative Study of Technetium-99m-WBCs and Indium-111-Granulocytes for the
Examination of Patients with Inflammatory Bowel Disease. In: Journal of
Nuclear Medicine, Vol 34, No 7 (July), 1993: pp 1052 - 1057.
Datz FL. Letter from the Guest Editor. In: Seminars in
Nuclear Medicine, Vol XXIV, No 2 (April), 1994: pp 89 - 91.
Datz FL. Indium-111 Labeled Leukocytes for the Detection of
Infection: Current Status. In: Seminars in Nuclear Medicine, Vol XXIV, No 2
(April), 1994: pp 92 - 109.
Oates E. Scintigraphic Diagnosis of Infection and
Inflammation. In: Applied Radiology, Vol ##, No ## (January), 1992: pp 48 -
53.
Peters AM. The Utility of Tc-99m HMPAO - Leukocytes for
Imaging Infection. In: Seminars in Nuclear Medicine, Vol XXIV, No 2
(April), 1994: pp 110 - 127.
Palestro CJ. The Current Role of Gallium Imaging in
Infection. In: Seminars in Nuclear Medicine, Vol XXIV, No 2 (April), 1994:
pp 128 - 141.
Zabel P. The Function,Physiology, and Isolation of
Granulocytes. In: The Journal of Nuclear Medicine Technology, Vol 16, No 4
(December), 1988: pp 206 - 215.
Zabel P, Robichaud N, Hiltz A. Facilities and Equipment for
Aseptic and Safe Handling of Blood Products. In: The Journal of Nuclear
Medicine Technology, Vol 20, No 4 (December), 1992: pp 236 - 241.
Zabel R, Robichaud N, Hiltz A. Personnel and Product
Protection During Manipulation of Blood Products. In: The Journal of
Nuclear Medicine Technology, Vol 21, No 1 (March), 1993: pp 33 - 37.
Videos
Internet URL's
Society of Nuclear Medicine,
Guidelines for Gallium
Scintigraphy
Society of Nuclear Medicine,
Guidelines for In-111 Leukocyte
Scintigraphy for Suspected Infection / Inflammation
Society of Nuclear Medicine,
Guidelines for Tc-99m Exametazime
(HMPAO) Labeled Leukocyte Scintigraphy for Suspected Infection /
Inflammation
Williams, Scott C. MD,
Gallium
67 Infection and Inflammation Imaging. From the Review and Reference Notes
on Nuclear Medicine, Madigan Army Medical Center, Tacoma WA.
Williams, Scott C. MD,
Indium-111
White Blood Cell Imaging. From the Review and Reference Notes on Nuclear
Medicine, Madigan Army Medical Center, Tacoma WA.
Williams, Scott C. MD,
Tc-HMPAO
White Blood Cell Imaging. From the Review and Reference Notes on Nuclear
Medicine, Madigan Army Medical Center, Tacoma WA.
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- What anticoagulants are generally considered acceptable for
white cell labelling? What are the advantages and disadvantages of each?
- What is the role of Hespan (hydroxyethyl starch / hetastarch)
in WBC labelling?
- Briefly outline the primary points of the debate surrounding
the use of laxatives or enemas to cleanse the bowel for delayed Ga-67 citrate
images.
|
lgoodin@idirect.com or