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Nuclear gastroenterology: novel techniques in clinical and experimental gastrointestinalmobility, IBD and hepatology

Bennink, R.J.

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Citation for published version (APA):Bennink, R. J. (2004). Nuclear gastroenterology: novel techniques in clinical and experimental gastrointestinalmobility, IBD and hepatology.

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Download date: 12 Jul 2020

Chapterr I

Introduction n

Roeloff Bennink

Departmentt of Nuclear Medicine

(Academicc Medical Center Amsterdam, The Netherlands)

Chapterr I

Introduction n

Nuclearr Gastroenterology

Mostt of the clinical manifestations of gastrointestinal (GI) disease reflect abnormal

function.. Dysphagia, dyspepsia, change in bowel habit, abdominal pain, GI bleeding, and

jaundicee are all manifestations of disturbed physiology. Whereas abnormal anatomy is

usuallyy best investigated by endoscopy, conventional radiology, ultrasound or computed

tomographyy (CT), some functional abnormalities are better defined and explored by

radionuclidee techniques. Magnetic resonance imaging (MR1) has a large potential in the

evaluationn of GI physiology and motility disorders." However, the expensive technique,

thee limited expertise and availability for this kind of investigations and the lack of

validationn hamper wide implementation to date.2 Traditionally, investigating GI function

requiress intubation for sampling or prolonged intraluminal pressure monitoring. These

techniquess involve a degree of discomfort to the patient. Contrast studies and

endoscopy,, although excellent for anatomical detail, give only a very limited indication of

functionall disturbances. Scintigraphic studies show relatively poor anatomical detail but

makee their major contribution in the demonstration of abnormal function.1

Majorr advances in positron emission tomography (PET) have resulted in a shift in

nuclearr medicine research with an exponential growth in submitted papers and with

oncologyy as leading investigatory subject at the cost of conventional nuclear medicine.1

Exceptt for GI oncology, P ET has no major indications yet for GI motility disorders.

However,, P ET can be used to localize a source of cerebral activity, wThich can be used in

researchh assessing the brain's processing of visceral sensation and the role of abnormal

viscerall sensation in the pathophysiology of functional bowel disease.

Scintigraphy,, however, has more potential than the routine clinical investigations

currentlyy available in most nuclear medicine facilities, frequently restricted to gastric

emptyingg studies, limited hepatobiliary scintigraphy and localization of ectopic gastric

mucosaa in a Meckel's diverticulum. The current applicability of scintigraphic methods in

gastroenterologyy is larger and includes for instance detection and quantification of

gastroesophageall and enterogastric reflux, esophageal clearance, gastric emptying, small

bowell and colonic transit, calculous and acalculous biliary disorders, localization of

10 0

Introduction n

ectopicc gastric mucosa in a Meckel's diverticulum, localization of sites of GI hemorrhage

andd identification of sites of inflammation in the GI tract.'

Researchh in GI motility, IBD and hepatology is making quantum leap progression

increasingg the demand for noninvasive validation of hypotheses and techniques.

Therefore,, the aim of this thesis was to further characterize existing nuclear medicine

techniquess in the evolving field of gastroenterology and to explore novel applications and

techniquess for clinical and experimental use in human and animal studies.

Gastrointestinall motility

Definition n

GII dysmotility symptoms are a major problem in routine clinical practice. If after

carefull history-taking, thorough physical examination, appropriate biochemical and

hematologicall screening and the conducting of examinations like radiology or endoscopy,

withh or without biopsy, no structural, infectious or biochemical cause can be found, the

diagnosiss of functional GI motilitv disorder can be made.6 The advantages of

radionuclidee imaging for studying GI tract function have remained the same since the

orall administration of 5 tCr porridge to measure gastric emptying was introduced 30 years

ago.. In contrast to manometry, scintigraphy is noninvasive, does not disturb normal

physiology,, and permits quantification of bulk transit of solids and liquids. Compared

withh radiographic methods, scintigraphy results in low radiation burden, is easily

quantified,, and uses commonly ingested foods rather than non-nutrient substrates.8

Evaluationn of severe functional GI motility disorders requires an investigation of the

entiree GI tract. To determine the correct therapeutic option, it is important to

differentiatee between a diffuse GI motor disorder and the dysfunction of an isolated GI

segment.99 Furthermore, it has been shown that whole gut transit scintigraphy frequently

leadss to a change in diagnosis and thus leads to improved patient management.10

11 1

Chapterr I

P a t i e n tt s tud ie s

Duall isotope scintigraphy is now widely used for clinical and investigative purposes. It

iss a noninvasive, phvsiologic, easy to perform, safe and quantitative technique with a low

radiationn burden.11 It has become the gold standard for the evaluation of gastric emptying

forfor solids and liquids in all types of gastrointestinal disorders and for assessing the

efficacyy of gastrokinetic drugs and surgical procedures. Further investigation of the

pathophysiologyy of functional dyspepsia focused on antral dysmotility, abnormal gastric

pacemakerr function and myoelectric activity.12 !> These investigations have led to the

conclusionn that delayed gastric emptying of a solid meal is related to antral

hypomotility."'' I t was demonstrated that dynamic gastric scintigraphy allows visualization

andd characterization of antral contractions.1 It can also be used simultaneously to

evaluatee the compartmentalization of food inside the stomach and to quantify the

emptyingg of a radiolabeled test meal from each compartment.18

Thee normal values for scintigraphic gastric emptying studies are based on male

controlss or a mixed control population. Historically it has been assumed that men and

womenn have identical rates of gastric emptying.1021 The effect of gender on gastric

emptyingg remains controversial though there is more and more evidence that women

havee slower gastric emptying rates for solids22'24 and possibly also for liquids.̂

Thee aims of the study presented in chap ter 2 w-ere (1) to confirm the difference in

gastricc emptying for solid and liquid test meal between healthy men and women,

andd (2) to investigate the origin of this difference in absence of pathology by studying

regionall gastric emptying and antral motility.

I nn chapter 2, we confirmed a significant difference in gastric emptying of a solid test

meall between healthy male and female volunteers. It has been demonstrated that gastric

emptyingg is slower in healthy premenopausal women, where both half-emptying time

(TV2)) and iag-phase (Tlag) are significandy more prolonged than in men. When

evaluatingg small-bowel transit as part of an entire bowel transit protocol, determination

off the 10% small bowel transit time (SBTT) for solid test meal could be different for

malee and female patients. Therefore, the purpose of the study presented in chap ter 3

wass to define normal values of small-bowel transit in men and women, and to assess if

theree is a gender difference, or a difference between solids and liquids.

12 2

Introduction n

Accuratee measurement of the orocecal transit time (OCTT) is an important step in

achievingg better insight in detecting dysmotility of the upper GI tract.26 J6 Moreover,

intestinall transit influences the functions of the colon by the supply of substrates. ''

Efficiencyy of colonic fermentation (i.e., the metabolism of unabsorbed dietary

components)) is greatly influenced by the motility of the upper intestinal tract. '40 Hence,

itt is of major importance to be able to measure transit times, OCTT in particular, using a

relativelyy simple, reproducible test. Methods for measuring intestinal transit should not

interferee with normal GI functions and should cause minimal discomfort for the patient.

Scintigraphyy is usually considered the reference technique for measuring OCTT.4 Several

drawbacks,, however, limit its application in routine practice. Expensive equipment, time

andd specialized personnel are required, and the use of radioactive isotopes is associated

withh some irradiation (<3 mSv). It is not preferable to repeat the technique at short

intervalss in children, and in pregnant women the use of this technique should be avoided

completely.. Therefore, it was the aim of the study presented in chapter 4 to investigate

thee validity of the lactulose-[13C]ureide (LU) breath test (LUBT) by direct comparison

withh a well-established method, namely scintigraphy using mTc-sulfur colloid.

Animall studies

Thee use of mouse models has increased in GI research, particularly in GI oncology

andd GI immunology.42 In contrast, GI motility research would benefit from further

developmentt and application of mouse models.42 In the recent literature, a variety of

techniquess have been used to assess gastric emptying in small laboratory animals. " In

mostt techniques, the animals are sacrificed, the stomach and intestine are removed and

weighed,, and the content is analyzed,43,46 by measuring its radioactivity,43 counting the

numberr of glass beads it comprises47 or assessing it with phenol red photospectrometry.

Otherr techniques limit the number of animals needed for an experiment by measuring

repetitivelyy without sacrificing the animal, such as by using scintigraphy in a rat parabiosis

model,444 MRI49 or 13C-octanoic acid breath testing in mice.48 The aims of the study

presentedd in chapter 5 were: (1) to adapt a routine pinhole gamma camera system,

suitablee for murine gastric-emptying scintigraphy without the need of sedation or

invasivee parabiotic preparation, (2) to validate murine gastric emptying scintigraphy by

13 3

Chapterr I

comparingg it to an established technique such as phenol red recover}-, and

(3)) to determine normal values for solid and liquid gastric emptying and evaluate effects

off multiple handling, earlier sedation and/or analgesia on gastric emptying.

Ann application of the model described and validated in chapter 5 is illustrated in

chapterr 6. In this study, our aim was to show in a murine model for postoperative ileus

thatt leukocyte infiltrates recruited in the intestinal muscularis by selective small-intestinal

manipulationn affect the motility of parts of the gastrointestinal tract, distant from the site

off manipulation, by triggering an inhibitor}' neural pathway. Gastrointestinal motility was

assessedd with pinhole gastric emptying scintigraphy in mice.

Gastricc volume scintigraphy

Dyspepsiaa refers to pain or discomfort centered in the upper abdomen in the absence

off structural or biochemical abnormalities.3° The pathophysiology of functional dyspepsia

iss largely unknown.51 l3 Proximal stomach dysfunction has been demonstrated in patients

withh functional dyspepsia, with impaired gastric accommodation to meal ingestion54 and

hypersensitivityy to fundic distention.55 However, controversy remains and therapeutic

effectss of drugs targeting these mechanisms are often disappointing.56,57

Thee gastric accommodation response enables relaxation of the proximal stomach,

providingg a reservoir for food ingestion without a rise in pressure/8 Impaired relaxation

off the proximal stomach may contribute to the development of meal-induced symptoms

inn conditions such as functional dyspepsia,54 diabetes meliitus59 or postfundoplication

syndrome.. To facilitate research on impaired gastric accommodation, a noninvasive and

easy-to-performm test is needed to select patients for pharmacological testing and evaluate

effectss of therapeutic strategies.6'

Measurementt of the gastric accommodation response to meal intake is technically

difficul tt and available techniques have methodological drawbacks.61 The current gold

standardd for the measurement of accommodation is the gastric barostat, involving the

introductionn of a balloon into the gastric fundus.62 In addition to the discomfort

associatedd with this invasive, and time-consuming procedure, the presence of a balloon in

thee stomach has been shown to cause dilatation of the antrum as a result of meal

displacementt and induction of exaggerated proximal gastric relaxation.63 Nonradiation

14 4

Introduction n

techniques,, such as ultrasound or MRI have technical limitations or, in the case of MRI,

potentiall advantages but limited availability for this type of studies.61,64

AA scintigraphic technique based on pertechnetate uptake in gastric mucosa for

measurementt of gastric accommodation has been described/'5"7<l However, this technique

requiress relative high exposure to ionizing radiadon and imaging can only be performed

withinn a relatively short time interval after isotope injection.61 Despite these limitations,

thee technique could be applicable in clinical practice to select patients with impaired

accommodationn that might benefit from fundic relaxant agents.

Thee aim of the study presented in chapter 7 was to refine the scintigraphic method,

limitingg the radiation dose applied and increasing possible postinjection imaging time

spann without losing image quality, so that sequential (multiple measurements within

11 test) and repetitive (measurements before and after treatment) measurements within

11 subject become possible without increasing radiation burden.

Thee technique of gastric volume scintigraphy has been shown to record changes in

postprandiall volume to a similar extent as the gastric barostat.66 It should be emphasized

thatt in this study the barostat balloon was positioned in the proximal stomach during

SPECTT scanning, providing a positive pressure to the gastric wall and thereby actively

distendingg the stomach. Under more physiological conditions, however, the stomach will

remainn collapsed. Consequendy, the volumes measured by SPECT scanning will reflect

intragastricc content such as intragastric secretions, swallowed air and ingested foods or

liquids.. Based on these assumptions, we hypothesized in chapter 8 that in the absence of

aa barostat balloon, SPECT scanning will largely detect the volume effect of meal

ingestionn and will be a rather insensitive tool to detect fundic relaxation. To test this

hypothesis,, the ability to detect fundic relaxation of comparable magnitude evoked by

meall ingestion or glucagon was compared between the two techniques performed at

separatee days. In addition, symptoms reported during the study were evaluated as indirect

measuree of procedure related discomfort.

15 5

Chapterr I

Inflammatoryy bowel disease

Patientt studies

Ulcerativee colitis (UC) is a chronic inflammatory bowel disease accompanied by

frequentt acute exacerbations. It is usually diagnosed by rectosigmoidoscopy, colonoscopy

orr double-contrast barium enema.

Colonoscopicc and contrast radiographic procedures have inherent disadvantages and

cann be cause of severe complications. In severe cases of the disease, colonoscopv should

nott be performed to assess the severity- and the extent of the disease. Caution must be

exercisedd in performing barium studies in acutely ill patients with severe colitis, because

bowell preparation may worsen the disease or precipitate toxic dilatation of the colon.

However,, knowing the severity of disease is important for estimating the intensity of

anti-inflammatoryy therapy and the risk of complications. Some recommendations for

therapyy are based on extent and severity- of disease activity. 2' 3

Despitee convincing evidence in the recent literature about the potential benefits of

WnTc-hexamethylpropylenee amine oxime (HMPAO)-labeled leukocyte scintigraphy in

adul ts,44 8 and children, 9'8,i the procedure is not performed routinely for UC in many

hospitals. .

Thee aim of the study presented in chapter 9 was to determine if 9" mTc-HMPAO

labeledd WBC scintigraphy could be an alternative to endoscopy with biopsy to determine

thee extent and the severity of the disease in these critically ill patients.

Treatmentt of ulcerative colitis is mainly based on corticosteroids, administered orally,

parenterallyy or rectally. " A rapid and sustained response is usually seen within a few days

followingg initiation of treatment. However, the overall rate of steroid treatment failure in

acutee exacerbations of UC remains high, and 20-30% of patients ultimately require

surgery.. ' 8~ The introduction of cyclosporine as a potent immunosuppressive drug for

treatmentt of corticosteroid-refractory UC benefits the short-term management in

60-80%% of patients."" M However, several questions remain regarding the long-term

maintenancee strategies, since long-term prognosis is not overall impressive and

cyclosporinee treatment is known for its possible important side effects.83,8l

16 6

Introduction n

Predictionn of the long-term prognosis of UC at the time of diagnosis and early

identificationn of which patients with a severe exacerbation wil l respond to therapy

remainss difficult . However, it is of great clinical importance to be able to predict a need

forr step-up medical treatment or colectomy at an early stage of the acute attack."''86

Therapeuticc action is based on reduction of inappropriate gut inflammation, by means

off glucocorticoids, immunomodulators like cyclosporine or biological therapeutic

interventionn in mucosal homing.87,88 Since scintigraphy and histology correlate very well

inn this particular field, WBC scintigraphy could become a reliable, noninvasive prognostic

tooll in prediction of therapeutic response and the follow-up of treatment for CU.

Thee aim of the study presented in chapter 10 was to determine if WBC scintigraphy

cann predict early treatment failure in patients with acute attacks of UC.

Gantryy validation

Duringg the development of new radiopharmaceuticals, the biological behavior and

dosimetryy are frequently studied by ex vivo measurements in animals.89'90 However, the

benefitss of an in vivo technique, such as single photon emission computed tomography

(SPECT),, are numerous. The number of animals needed within an in vivo approach is far

lesss compared to ex vivo measurements, where for a single measurement the animal has

too be sacrificed. The reduced number of animals required within an in vivo approach is

beneficiall from an ethical point of view, but may also save research time and may

thereforee be more cost-effective.

AA prerequisite for the replacement of ex vivo experiments by SPECT imaging is that it

enabless an accurate quantification of tracer uptake and kinetics. For in vivo experiments

withh smaller animals, such as mice, hamsters, or rats, a SPECT system encounters its

physicall limit s for resolution and sensitivity. The pinhole collimator has been used

extensivelyy to obtain greater detail in planar imaging. The application of pinhole SPECT,

however,, is difficul t since it requires a heavy collimated detector to rotate around a small

objectt with a precisely constant radius of rotation. To circumvent this problem, we have

developedd an animal pinhole SPECT system in which the mechanical misalignment is

minimized. .

17 7

Chapterr I

Chapterr 11 describes a dedicated animal pinhole SPECT device, in which the gantry

andd collimator are fixed and the animal rotates. To ensure that the rotation of the object

doess not introduce artifacts, calibration experiments were performed. Phantom

experimentss were done to investigate the extent to which accurate quantification of

tracerr uptake mav be possible with this new svstem. In vivo experiments were performed

usingg 2 animals of different size, a rat and a hamster, to test the clinical feasibility of the

svstem. .

Animall studies

Althoughh the initiating events of IB D are still unknown, increasing evidence indicates

thatt mucosal CD4+ T cells activated by enteric bacteria initiate and perpetuate the

inflammationn in genetically susceptible individuals. Molecular understanding of the

mechanismss that guide lymphocyte trafficking into the gut is rapidly increasing.8*

Molecularr control of lymphocyte trafficking in mucosal tissues under physiological and

pathologicall condit ions is a well-orchestrated interaction between lymphocyte receptors

andd corresponding endothelial ligands.88 In an inflammatory state endothelial adhesion

moleculess are upregulated and lymphocytes home to their target tissue.*8 Imbalance of

thee immunomodulat ing mechanisms can result into a chronic nonspecific inflammation

inn IBD where a down-regulated response would be appropriate. " Aberrant (excessive or

inappropriate)) homing of these cells to mucosal sites is believed to be a central element

inn the pathogenesis of IBD.'14 This knowledge has fuelled enthusiasm for the

developmentt of novel anti-inflammatory strategies, by blunting the multistep lymphocyte

adhesionn cascade.88 To this end, designer drugs for IBD are created and subsequendy

testedd in animal models for clinical potential. However, these animals are expensive and

largee numbers can be required.

AA noninvasive technique, able to assess inflammatory activity in bowel segments or

lymphocytee recirculation and kinetics in the follow-up of experimental treatment for

IBD ,, would not onlv benefit longitudinal studies, but also reduce the number of animals

requiredd for testing.93 Radioactive labeled purified lymphocytes have been shown to allow

studyy of inflammatory activity, short-term lymphocyte recirculation kinetics and

homing.944 n ' l n -ox ine is the most appropriate reagent for radiolabeling lymphocytes for in

18 8

Introduction n

vivoo distribution studies. The 2,4,6-trinkrobenzene sulfonic acid (TNBS) model of colitis

iss characterized by a T helper 1 (TH1) cell mediated transmural colitis and resembles

humann Crohn's disease in regard to many features, both on a histological and

immunologicall level.97' Dedicated pinhole single photon emission computed tomography

(SPECT)) cameras have been shown to be able to image radioactivity distribution in vivo

inn small animals with a spatial resolution on the order of a few mm.96'' ): Therefore, the

aimm of the study presented in chapter 12 was to construct and validate an animal model

forr IBD , in which intestinal lymphocyte homing can be monitored non-invasively in vivo

byy means of pinhole SPECT.

Underr normal conditions, naive T lymphocytes migrate randomly from blood to

secondaryy lymphoid tissues for immune surveillance. When naive T lymphocytes

encounterr an antigen in the draining lymph nodes of the gut, they differentiate into

memory/effectorr cells. If such an encounter takes place in the mesenterial lymph nodes,

migrationn is subsequendy directed back to the intestinal mucosa.'8 This process is

controlledd by the expression of different sets of adhesion molecules and chemokines.99,10°

Thee integrin alpha(a)4 beta((3)7 is the principal gut-homing receptor and functions at

severall steps in the adhesion cascade by interacting with the mucosal addressin

MAdCAM- 11 present on endothelial cells. ° ' " Naive lymphocytes express low levels of

oc4[377 but upon activation a significant amount of functionallv active a4|37 appears on the

surface."'̂ ^ During intestinal inflammation MAdCAM- 1 is upregulated resulting in an

increasedd influx of lymphocytes.

I nn inflammatory bowel disease, increased numbers of activated CD4+ TH1

lymphocytes,, that locally produce proinflammatory cytokines, such as interferon y

(IFN-v)) and tumor necrosis factor a (TNF-a), mediate mucosal inflammation and tissue

damage.'' Blockade of lymphocyte recruitment to the intestinal mucosa is considered a

usefull therapy for inflammatory bowel disease. Indeed, administration of antibodies that

bindd either the oe4 integrin alone or in combination with [37 has resulted in therapeutic

benefitt in experimental colitis104"106 and in patients with active Crohn's disease.10

Althoughh these results are promising, the number of in vivo studies is limited. More

insightt into the complex migratory pathways of lymphocytes to the intestine and the role

chemokiness and their receptors play herein, is necessary.

19 9

Chapterr I

I nn the studv presented in chapter 13, we used dedicated animal SPECT for

assessmentt of radioactive labeled inln~oxinate purified T helper lymphocyte homing to

thee gut in TNBS-induced experimental colitis in mice. Further, we applied this technique

too study blockade of intestinal lymphocyte influx in TNBS colitis with an anti-oc4 integrin

antibody. .

Liverr disease

Assessmentt of hepatocellular function

Hepaticc resection is the therapy of choice for malignant and symptomatic benign,

hepatobiliaryy tumors. Recent years have shown a marked decrease in morbidity and

mortalityy rates after major liver resections.1"8' u'9 Refinements in operative techniques,

betterr selection of patients and advances in perioperative care are thought to be

responsiblee for this improvement."" Nevertheless, perioperative blood loss and

postoperativee liver failure have remained the most significant complications after liver

resections,, particularly in patients with suboptimal liver function due to parenchymal

liverr disease such as cirrhosis or steatosis.111 The major cause of mortality after liver

resectionn consequently is liver failure."* For this reason it is important to estimate total

andd regional liver function before planning partial resection of the liver in order to

predictt function of the remnant liver.

T oo date, the most frequendy used test for evaluating preoperative liver function is the

indocyaninee green (ICG) clearance test.112 Alternatively, , )mTc-labeled iminodiacetic acid

(IDA )) analogues, transported in blood by binding to albumin in the same manner as

ICG,, can be used for hepatobiliary scintigraphy (HBS) in the assessment of liver

function,1133 HBS, requiring a single intravenous injection, provides visual and quantitative

informationn of global and regional liver function as well as excretory function

(intrahepaticc and extrahepatic bile transport). Both ICG and "Tc -mebro fen in are

excretedd in bile by the hepatocytes114 by the ATP-dependent export pump multidrug-

resistancee associated protein 2, without undergoing biotransformation during their transit

throughh the hepatocyte.11^ " 6 Therefore, these agents are well suited for the study of

20 0

Introduction n

hepaticc transport. The aim of the study presented in chapter 14 was to examine

correlationn of the ICG clearance test with the uptake of ""Tc-mebrofenin as determined

fromm the blood as well as from scintigraphical assessment.

Thee maximum extent of resection compatible with a safe postoperative outcome

remainss unknown, but it is generally believed that the risk for perioperative

complicationss increases when the remnant liver volume is too small.11' Therefore,

preoperativee assessment of hepatic function and remnant liver volume (RLV) is

advocated.1188 Measurement of preoperative and remnant liver volumes can be accurately

estimatedd by CT.m'12<) However, most strategies evaluating preoperative hepatic function

reservee and estimating the RLV rely on a homogeneous liver function.121 Unlike patients

undergoingg liver resection for metastatic cancer or benign liver conditions, patients with

hepatocellularr carcinoma (HCC) or obstructing tumors like cholangiocarcinoma may

havee underlying chronic liver disease or cholestasis with primary or secondary impaired

totall or segmental liver function.

Theree is a good correlation between the preoperative 99mTc-mebrofenin liver uptake

ratee and the ICG clearance test in patients scheduled for major liver surgery.123

Therefore,, the aim of the study presented in chapter 15 was to assess total and regional

liverr function before and after major liver surgery and to compare scintigraphic results

withh volumetric data and ICG clearance test results. Furthermore, the correlation

betweenn the immediate postoperative remnant liver function predicted on preoperative

scintigraphyy and measured 24 h after surgery with scintigraphy was assessed. Finally, the

relationn between liver function regeneration determined with HBS and volumetry was

assessed. .

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21 1

Chapterr I

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