Physiology and pathophysiology of the ileal brake in humans Vu, M.K.

Physiology and pathophysiology of the ileal brake in humans

Vu, M.K.

Citation

Vu, M. K. (2007, September 25). Physiology and pathophysiology of the ileal brake in

humans. Department Gastroentero-hepatolgy, Medicine / Leiden University Medical Center

(LUMC), Leiden University. Retrieved from https://hdl.handle.net/1887/12350

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the

Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/12350

Note: To cite this publication please use the final published version (if applicable).

Chapter 9

GALLBLADDER MOTILITY IN CROHN'S DISEASE: Influence of

disease localisation and bowel resection

M. K. Vu

¹

, H. A. J. Gielkens

¹

, R. A. van Hogezand

¹

, J. A. van Oostayen

²

, C.

B. H. W. Lamers

¹

, A. A. M. Masclee

¹

Departments of Gastroenterology-Hepatology

¹

and Radiology

²

, Leiden

University Medical Center, Leiden, the Netherlands

Scand J Gastroenterol. 2000 Nov;35(11):1157-62

152

153

'ALLBLADDER -OTILITY IN #ROHN $ISEASE )NmUENCE OF $ISEASE ,OCALIZATION

AND "OWEL 2ESECTION

- + 6U ( ! * 'IELKENS 2 ! VAN (OGEZAND * ! VAN /OSTAYEN # " ( 7 ,AMERS

 ! ! - -ASCLEE

$EPT OF 'ASTROENTEROLOGYn(EPATOLOGY AND 2ADIOLOGY ,EIDEN 5NIVERSITY -EDICAL #ENTER ,EIDEN 4HE .ETHERLANDS

6U -+ 'IELKENS (!* VAN (OGEZAND 2! VAN /OSTAYEN *! ,AMERS #"(7 -ASCLEE !!-

'ALLBLADDER MOTILITY IN #ROHN DISEASE INFLUENCE OF DISEASE LOCALIZATION AND BOWEL RESECTION 3CAND * 'ASTROENTEROL n

"ACKGROUND 0ATIENTS WITH #ROHN DISEASE #$ HAVE AN INCREASED RISK OF DEVELOPING GALLSTONES !MONG OTHER FACTORS GALLBLADDER MOTILITY MAY HAVE A ROLE IN THE PATHOGENESIS OF GALLSTONE FORMATION 7E HAVE EVALUATED WHETHER GALLBLADDER MOTOR FUNCTION IS AFFECTED IN #ROHN DISEASE WITH SPECIAL EMPHASIS ON THE INmUENCE OF DISEASE LOCALIZATION AND PREVIOUS BOWEL RESECTION -ETHODS 4HIRTY SEVEN PATIENTS 

FEMALES AND  MALES AGE    YEARS WITH INACTIVE #ROHN DISEASE #$!)
 WERE STUDIED 

PATIENTS AFTER ILEOCECAL RESECTION AND  NON OPERATED PATIENTS  HAD SMALL BOWEL DISEASE AND  HAD LARGE BOWEL DISEASE .INETEEN HEALTHY SUBJECTS  FEMALE  MALE AGE    YEARS SERVED AS CONTROLS

'ALLBLADDER VOLUMES WERE MEASURED IN THE FASTING STATE AND AT REGULAR INTERVALS FOR  H AFTER INGESTION OF A SOLID MEAL  KCAL  "LOOD SAMPLES WERE DRAWN AT REGULAR INTERVALS FOR DETERMINATION OF CHOLECYSTOKININ

##+ AND PEPTIDE 99 099  2ESULTS &ASTING GALLBLADDER VOLUMES WERE SIGNIlCANTLY 0


REDUCED IN PATIENTS WITH LARGE BOWEL DISEASE    ML OR AFTER ILEOCECAL RESECTION    ML COMPARED TO PATIENTS WITH SMALL BOWEL DISEASE    ML AND CONTROLS    ML  &ASTING PLASMA ##+ LEVELS WERE SIGNIlCANTLY 0
 HIGHER IN PATIENTS WITH LARGE BOWEL DISEASE OR AFTER ILEOCECAL RESECTION COMPARED TO PATIENTS WITH SMALL BOWEL DISEASE AND CONTROLS 0OSTPRANDIAL GALLBLADDER EMPTYING AND ENDOGENOUS PLASMA ##+ AND 099 SECRETION IN PATIENTS WITH #ROHN DISEASE WERE NOT DIFFERENT FROM CONTROLS #ONCLUSIONS &ASTING GALLBLADDER VOLUME IS DECREASED AND FASTING PLASMA ##+

LEVELS ARE INCREASED IN PATIENTS WITH #ROHN DISEASE OF THE LARGE BOWEL AND PATIENTS AFTER ILEOCECAL RESECTION

0OSTPRANDIAL GALLBLADDER MOTILITY ##+ AND 099 RELEASE WERE NOT AFFECTED IN PATIENTS WITH #ROHN DISEASE

+EY WORDS 'ALLBLADDER MOTILITY #ROHN DISEASE CHOLECYSTOKININ PEPTIDE 99

! ! - -ASCLEE -$ 0H$ $EPT OF 'ASTROENTEROLOGYn(EPATOLOGY ,EIDEN 5NIVERSITY -EDICAL

#ENTER 0/ "OX   2# ,EIDEN 4HE .ETHERLANDS FAX   

0

ATIENTS WITH #ROHN DISEASE HAVE AN INCREASED RISK OF DEVELOPING GALLSTONES n  3EVERAL STUDIES HAVE REPORTED A GALLSTONE PREVALENCE OF ABOUT  IN PATIENTS WITH #ROHN DISEASE COMPARED TO  AMONG AGE MATCHED HEALTHY SUBJECTS n  4HIS REPORTED PREVALENCE IS HOWEVER NOT EQUALLY DISTRIBUTED AMONG THE GROUP OF PATIENTS WITH #ROHN DISEASE 0ATIENTS WITH #ROHN DISEASE CONlNED TO THE ILEUM OR AFTER ILEAL RESECTION HAVE A HIGHER PREVALENCE OF GALLSTONES OF AROUND  WHILE THE PRE VALENCE IS ONLY  IN PATIENTS WITH THE DISEASE CONlNED TO THE COLON   

0ATHOPHYSIOLOGICAL FACTORS UNDERLYING CHOLESTEROL GALLSTONE DISEASE IN GENERAL ARE EXCESS BILIARY CHOLESTEROL SECRETION RESULTING IN CHOLESTEROL SUPERSATURATION INCREASE IN NUCLEA TION PROMOTING FACTORS AND ALTERATIONS IN GALLBLADDER MOTILITY

   )N PATIENTS WITH #ROHN DISEASE DISTURBANCES IN THE ENTEROHEPATIC CIRCULATION OF BILE SALTS OWING TO DISEASE OR

RESECTION OF THE ILEUM RESULTING IN BILE SALT MALABSORPTION AND INCREASED BILIARY CHOLESTEROL HAVE BEEN PROPOSED AS THE MOST IMPORTANT MECHANISM    4HE ROLE OF GALLBLADDER MOTILITY IN THE PATHOGENESIS OF GALLSTONE FORMATION IN #ROHN DISEASE IS LESS CLEAR BECAUSE THE PUBLISHED DATA ARE CONmICTING n  )N THREE STUDIES IMPAIRED POSTPRANDIAL GALLBLADDER CONTRAC TION IN PATIENTS WITH #ROHN DISEASE WAS REPORTED WHILE NO EVIDENCE FOR ABNORMAL GALLBLADDER EMPTYING WAS FOUND IN OTHER STUDIES n  4HE AIM OF THE PRESENT STUDY WAS THEREFORE TO EVALUATE FASTING AND MEAL STIMULATED GALLBLADDER MOTILITY IN A LARGE GROUP OF #ROHN DISEASE PATIENTS WITH DIFFERENT DISEASE LOCALIZATION AND WITH OR WITHOUT ILEOCECAL RESECTION !S THE GALLBLADDER MOTOR RESPONSE TO A MEAL IS MAINLY CONTROLLED BY VARIOUS GUT HORMONES RELEASED DURING THE INTESTINAL PHASE BASAL AND MEAL STIMULATED PLASMA CONCENTRATIONS OF PROXIMAL AND DISTAL GUT HORMONES WERE ALSO MEASURED

154

3UBJECTS AND -ETHODS 3UBJECTS

4HIRTY SEVEN PATIENTS WITH INACTIVE #ROHN DISEASE #ROHN DISEASE ACTIVITY INDEX #$!) MEDIAN  RANGE n

WERE INCLUDED 0ATIENTS WITH CONCOMITANT DISEASES SUCH AS DIABETES MELLITUS AND HYPERTENSION WERE EXCLUDED FROM THE STUDY .ONE OF THE PATIENTS HAD CLINICAL SYMPTOMS OR ULTRASONOGRAPHICAL EVIDENCE OF GALLSTONES &IFTEEN OF THE 

PATIENTS HAD PREVIOUSLY UNDERGONE ILEOCECAL RESECTION MED IAN  YEARS RANGE n YEARS  4HE MEAN LENGTH OF THE RESECTED ILEOCECAL SEGMENT WAS    CM 4WELVE OF THE REMAINING  PATIENTS HAD SMALL BOWEL DISEASE AND  HAD COLONIC DISEASE !T THE TIME OF THE EXPERIMENT  PATIENTS WERE ON MEDICATION AMONG WHICH  PATIENTS WERE ON PREDNISONE  ON  !3! DERIVATIVES AND  ON BOTH PREDNISONE AND  !3! DERIVATIVES .INE OF THE FEMALE PATIENTS USED ORAL CONTRACEPTIVES !LL MEDICATIONS WERE CONTINUED EXCEPT ON THE MORNING OF THE EXPERIMENT &URTHER CLINICAL CHARACTERISTICS OF THE THREE PATIENT GROUPS ARE PRESENTED IN 4ABLE )

.INETEEN HEALTHY SUBJECTS WITHOUT ANY HISTORY OF GASTRO INTESTINAL DISEASE OR ABDOMINAL SURGERY SERVED AS CONTROLS

4ABLE )  4HE USE OF ORAL CONTRACEPTIVES WAS REPORTED IN  OF THE  FEMALE HEALTHY SUBJECTS 3TUDIES WERE PERFORMED IRRESPECTIVE OF THE TIME OF THE MENSTRUAL CYCLE 4HE STUDY PROTOCOL HAD BEEN APPROVED BY THE ETHICS COMMITTEE OF THE ,EIDEN 5NIVERSITY -EDICAL #ENTER

3TUDY PROTOCOL

!LL SUBJECTS WERE STUDIED AT  H AFTER AN OVERNIGHT FAST

!FTER TWO MEASUREMENTS OF BASAL GALLBLADDER VOLUME AN INTRAVENOUS CANNULA WAS INSERTED INTO THE ANTECUBITAL VEIN OF ONE ARM FOR BLOOD SAMPLING ! SOLID MEAL CONSISTING OF  G FAT  G PROTEIN AND  G CARBOHYDRATES  KCAL WAS INGESTED AT TIME T   MIN 'ALLBLADDER VOLUMES WERE MEASURED AND BLOOD SAMPLES FOR DETERMINATION OF GUT HOR MONES CHOLECYSTOKININ ##+  PANCREATIC POLYPEPTIDE 00 AND PEPTIDE 99 099 WERE DRAWN AT T 
   

      AND  MIN AFTER MEAL INGESTION

'ALLBLADDER VOLUME

'ALLBLADDER VOLUMES MEASURED BY REAL TIME ULTRASONOGRA PHY 4OSHIBA  -(Z TRANSDUCER WERE CALCULATED BY THE

SUM OF CYLINDERS METHOD USING A COMPUTERIZED SYSTEM 

  )N THIS METHOD THE LONGITUDINAL IMAGE OF THE GALLBLADDER IS DIVIDED INTO SERIES OF EQUAL HEIGHT WITH DIAMETER PERPENDICULAR TO THE LONGITUDINAL AXIS OF THE GALLBLADDER IMAGE 4HE UNCORRECTED VOLUME IS THE SUM OF VOLUMES OF THESE SEPARATE CYLINDERS 4O CORRECT FOR THE DISPLACEMENT OF THE LONGITUDINAL IMAGE OF THE GALLBLADDER FROM THE CENTRAL AXIS A CORRECTION FACTOR IS CALCULATED FROM THE LONGITUDINAL AND TRANSVERSAL SCANS OF THE GALLBLADDER 'ALLBLADDER VOLUME IS CALCULATED BY MULTIPLICATION OF THE UNCORRECTED VOLUME WITH THE SQUARE OF THE CORRECTION FACTOR 4HE MEAN OF TWO MEASUREMENTS WAS USED FOR ANALYSIS 4HE ASSUMPTIONS AND THE MATHEMATICAL FORMULA USED TO CALCULATE GALLBLADDER VOLUME HAVE BEEN DESCRIBED AND VALIDATED PREVIOUSLY 

 

(ORMONE ASSAYS

"LOOD SAMPLES FOR MEASUREMENT OF PLASMA PANCREATIC POLYPEPTIDE 00  CHOLECYSTOKININ ##+ AND PEPTIDE 99

099 WERE DRAWN AT TIME T 
       

 AND  MIN DURING EACH EXPERIMENT 4HE BLOOD SAMPLES WERE COLLECTED IN %$4! CONTAINING ICE CHILLED TUBES 4HE SAMPLES WERE CENTRIFUGATED AT A RATE OF  RPM FOR  MIN AT A TEMPERATURE OF  o# 0LASMA ##+ WAS MEASURED BY A SENSITIVE AND SPECIlC RADIOIMMUNOASSAY   4HIS ANTIBODY BINDS TO ALL ##+ PEPTIDES INCLUDING SULPHATED ##+ OCTAPEP TIDE BUT NOT GASTRIN 4HE DETECTION LIMIT OF THE ASSAY IS  P-

PLASMA 0LASMA 099 WAS MEASURED BY RADIOIMMUNOASSAY

099 ANTISERUM WAS GENERATED IN RABBITS BY INTRACUTANEOUS INJECTIONS OF SYNTHETIC HUMAN 099 "!#(%- !'

3WITZERLAND  099 WAS LABELLED WITH^) USING CHLORAMINE 4 4HERE IS NO CROSS REACTIVITY WITH 00 OR 6)0 4HE DETECTION LIMIT IS  P-PLASMA "OTH 099 n AND 099 n BIND TO THE ANTIBODY IN DILUTIONS UP TO  0LASMA 00 WAS DETERMINED BY RADIOIMMUNOASSAY AS DESCRIBED PREVIOUSLY

 

$ATA AND STATISTICAL ANALYSIS

$ATA ARE EXPRESSED AS MEAN  STANDARD ERROR OF THE MEAN

0OSTPRANDIAL GALLBLADDER EMPTYING WAS CALCULATED AS THE PERCENTAGE OF THE BASAL VOLUME )NTEGRATED INCREMENTAL VALUES FOR PLASMA HORMONE SECRETION WERE CALCULATED AS THE AREA UNDER THE PLASMA CONCENTRATION CURVE AFTER SUBTRACTION OF THE BASAL VALUE AT T   -ULTIPLE ANALYSIS OF VARIANCE -!./

4ABLE ) #HARACTERISTICS OF THE THREE PATIENT GROUPS AND OF THE HEALTHY CONTROLS $ISEASE DURATION AND #$!) ARE EXPRESSED AS MEDIANS AND RANGES AGE AND BODY MASS INDEX ARE EXPRESSED AS MEAN  STANDARD ERROR OF THE MEAN

#ONTROLS

.  

)LEAL #$

.  

#OLONIC #$

.  

)LEOCECAL RESECTION

.  

!GE YEARS            

3EX &-    

"ODY MASS INDEX KGM^            

$ISEASE DURATION YEARS ˆ  n  n  n

#$!) ˆ  n  n  n

155

6! WAS USED TO COMPARE GALLBLADDER VOLUME PLASMA 00 AND

##+ LEVELS BETWEEN AND WITHIN GROUPS AND TO ANALYSE THE INmUENCE OF AGE GENDER AND THE USE OF MEDICATION ON GALLBLADDER VOLUME #OEFlCIENT OF LINEAR CORRELATION 3PEAR MAN WAS USED TO CALCULATE THE CORRELATIONS BETWEEN FASTING GALLBLADDER VOLUMES AND THE LENGTH OF THE RESECTED SEGMENT AND #$!) 4HE LEVEL OF SIGNIlCANCE WAS SET AT 0


2ESULTS

&ASTING GALLBLADDER VOLUME

-EAN BASAL GALLBLADDER VOLUME WAS SIGNIlCANTLY

0
 SMALLER IN PATIENTS WITH LARGE BOWEL DISEASE AND AFTER ILEOCECAL RESECTION COMPARED TO PATIENTS WITH SMALL BOWEL DISEASE AND TO CONTROLS 4ABLE ))  )NDIVIDUAL DATA OF FASTING GALLBLADDER VOLUMES ARE SHOWN IN &IG  .O CORRE LATION WAS FOUND BETWEEN FASTING GALLBLADDER VOLUME AND

#$!) R   0   OR LENGTH OF THE RESECTED SEGMENT

R   0   

0OSTPRANDIAL GALLBLADDER EMPTYING

!FTER MEAL INGESTION GALLBLADDER VOLUME DECREASED SIG NIlCANTLY 0
 IN ALL #ROHN DISEASE PATIENTS AND HEALTHY

CONTROLS &IG   4HE DEGREE OF POSTPRANDIAL GALLBLADDER EMPTYING WAS NOT SIGNIlCANTLY DIFFERENT BETWEEN THE PATIENT GROUPS AND CONTROLS 2ESIDUAL GALLBLADDER VOLUMES AND MAXIMAL POSTPRANDIAL GALLBLADDER EMPTYING FOR ALL GROUPS ARE GIVEN IN 4ABLE ))

0LASMA 00

"ASAL PLASMA 00 LEVELS WERE NOT SIGNIlCANTLY DIFFERENT BETWEEN THE FOUR GROUPS 4ABLE )))  0LASMA 00 LEVELS SIGNIlCANTLY INCREASED 0
 IN RESPONSE TO THE MEAL IN ALL PATIENTS AND CONTROL SUBJECTS 0OSTPRANDIAL INTEGRATED PLASMA 00 CONCENTRATION WAS NOT SIGNIlCANTLY DIFFERENT BETWEEN THE GROUPS 4ABLE ))) 

0LASMA ##+

"ASAL PLASMA ##+ LEVELS WERE SIGNIlCANTLY 0


HIGHER IN PATIENTS WITH LARGE BOWEL #ROHN DISEASE AND AFTER ILEOCECAL RESECTION COMPARED TO PATIENTS WITH SMALL BOWEL DISEASE AND CONTROLS 4ABLE )))  0LASMA ##+ LEVELS SIG NIlCANTLY 0
 INCREASED IN RESPONSE TO THE MEAL IN ALL FOUR GROUPS &IG   0OSTPRANDIAL INTEGRATED PLASMA ##+

CONCENTRATIONS WERE NOT SIGNIlCANTLY DIFFERENT BETWEEN PATIENTS AND CONTROLS 4ABLE ))) 

4ABLE )) &ASTING AND RESIDUAL GALLBLADDER VOLUMES AND MAXIMAL PERCENTAGE OF POSTPRANDIAL GALLBLADDER EMPTYING IN THE THREE PATIENT GROUPS AND HEALTHY CONTROLS $ATA ARE EXPRESSED AS MEAN  STANDARD ERROR OF THE MEAN

#ONTROLS

.   )LEAL #$

.   #OLONIC #$

.   )LEOCECAL RESECTION

.  

&ASTING VOLUME ML            

2ESIDUAL VOLUME ML            

-AXIMAL EMPTYING             

0
 COMPARED TO PATIENTS WITH ILEAL #ROHN DISEASE #$ AND CONTROLS

&IG  )NDIVIDUAL DATA OF FASTING GALLBLADDER VOLUME ML MEAN

 STANDARD ERROR OF THE MEAN IN PATIENTS WITH #ROHN DISEASE OF THE ILEUM AND COLON PATIENTS AFTER ILEOCECAL RESECTION AND HEALTHY CONTROLS

&IG  'ALLBLADDER VOLUME ML MEAN  STANDARD ERROR OF THE MEAN DURING FASTING AND AFTER MEAL INGESTION IN PATIENTS WITH #ROHN DISEASE OF THE ILEUM CLOSED TRIANGLES  OF THE COLON BIG SQUARES  IN PATIENTS AFTER ILEOCECAL RESECTION CROSSES AND HEALTHY CONTROLS

SMALL SQUARES  0
 COMPARED TO PATIENTS WITH ILEAL #ROHN DISEASE AND CONTROLS

156

0LASMA 099

"ASAL PLASMA 099 LEVELS WERE NOT SIGNIlCANTLY DIFFERENT BETWEEN #ROHN DISEASE PATIENTS AND CONTROL SUBJECTS 4ABLE )))  ! SIGNIlCANT 0
 RISE IN PLASMA LEVELS OF 099 WAS FOUND IN THE LAST  MIN AFTER MEAL INGESTION T    AND

 MIN IN ALL THE PATIENT GROUPS AND IN THE HEALTHY CONTROLS

0OSTPRANDIAL INTEGRATED PLASMA 099 CONCENTRATIONS WERE NOT SIGNIlCANTLY DIFFERENT BETWEEN THE FOUR GROUPS 4ABLE ))) 

$ISCUSSION

4HE RESULTS OF THE PRESENT STUDY SHOW THAT FASTING GALLBLADDER VOLUME IS SIGNIlCANTLY SMALLER IN PATIENTS WITH #ROHN DISEASE OF THE LARGE BOWEL AND IN PATIENTS AFTER ILEOCECAL RESECTION COMPARED TO PATIENTS WITH SMALL BOWEL DISEASE AND TO CONTROLS /N THE OTHER HAND GALLBLADDER EMPTYING IN RESPONSE TO A MEAL IS NOT SIGNIlCANTLY DIFFERENT BETWEEN THE PATIENTS AND THE CONTROLS 7E HAVE INCLUDED IN THIS STUDY ONLY PATIENTS WITH INACTIVE #ROHN DISEASE AND WITHOUT EVIDENCE OF CHOLESTEROL GALLSTONES 0ATIENTS WHO HAD DEVELOPED CHOLESTER OL GALLSTONES WERE EXCLUDED SINCE IT HAS BEEN DOCUMENTED THAT CHOLESTEROL GALLSTONES AFFECT GALLBLADDER MOTILITY  

&ASTING GALLBLADDER TONE AND VOLUME ARE CONTROLLED BY BOTH HORMONAL AND NEURAL PATHWAYS !LTERATIONS IN ONE OF THESE FACTORS MAY AFFECT GALLBLADDER MOTILITY )NDEED PLASMA ##+

LEVELS WERE SIGNIlCANTLY HIGHER IN PATIENTS WITH LARGE BOWEL DISEASE OR AFTER ILEOCECAL RESECTION COMPARED TO PATIENTS WITH SMALL BOWEL DISEASE AND TO CONTROLS ##+ IS RELEASED FROM THE UPPER SMALL BOWEL AND IS THE MOST IMPORTANT HORMONAL MEDIATOR OF GALLBLADDER MOTILITY   ##+ IS NOT ONLY INVOLVED IN POSTPRANDIAL GALLBLADDER MOTILITY BUT ALSO PLAYS AN IMPORTANT ROLE IN REGULATING BASAL GALLBLADDER VOLUME )N HUMANS ADMINISTRATION OF THE ##+ ANTAGONIST LOXIGLUMIDE SIGNIlCANTLY INCREASES GALLBLADDER VOLUME   4HE ELEVATED FASTING PLASMA ##+ LEVELS IN PATIENTS WITH LARGE BOWEL DISEASE AND AFTER ILEOCECAL RESECTION CORRELATE WITH SMALL FASTING GALLBLADDER VOLUME FOUND IN THESE GROUPS 4HIS lNDING IS IN AGREEMENT WITH A PREVIOUS STUDY BY 3ALEMANS ET AL 

WHO FOUND THAT BASAL PLASMA ##+ IS INCREASED AND FASTING GALLBLADDER VOLUME IS DECREASED IN PATIENTS AFTER PROTOCO LECTOMY WITH ILEAL POUCH ANAL ANASTOMOSIS SUGGESTING A ROLE FOR THE COLON IN CONTROLLING PLASMA ##+ RELEASE FROM THE PROXIMAL GUT

'ASTROINTESTINAL PEPTIDES ARE RELEASED ALSO FROM THE DISTAL SMALL BOWEL AND LARGE BOWEL 0EPTIDE 99 099 IS SUCH A DISTAL GUT HORMONE )T IS A MEDIATOR OF THE SO CALLED ILEAL AND COLONIC BRAKEnA NEGATIVE FEEDBACK FROM THE DISTAL TO THE PROXIMAL GASTROINTESTINAL TRACT    4HE HIGHEST CONCEN TRATIONS OF 099 PRODUCING CELLS ARE FOUND IN THE ILEUM COLON AND RECTUM   )T HAS BEEN SHOWN IN DOGS THAT 099 INFUSION INDUCES GALLBLADDER RELAXATION AFTER ##+ STIMULATED GALL BLADDER CONTRACTION   )N THE PRESENT STUDY FASTING PLASMA 099 LEVELS WERE NOT SIGNIlCANTLY DIFFERENT BETWEEN PATIENTS WITH LARGE BOWEL DISEASE OR AFTER ILEOCECAL RESECTION COMPARED TO PATIENTS WITH SMALL BOWEL DISEASE AND TO CONTROLS SUGGESTING THAT 099 DOES NOT ACCOUNT FOR THE DIFFERENCES IN FASTING GALLBLADDER VOLUME FOUND BETWEEN THESE PATIENT GROUPS

4HE VAGUS NERVE IS AN IMPORTANT CHOLINERGIC NEURAL MEDIATOR OF FASTING GALLBLADDER MOTOR ACTIVITY   )N BOTH HUMANS AND DOGS GALLBLADDER VOLUME IS INCREASED AFTER TRUNCAL VAGOTOMY OR DURING CHOLINERGIC BLOCKAGE WITH ATROPINE WHILE IT IS DECREASED DURING ADMINISTRATION OF THE VAGAL CHOLINERGIC STIMULUS BETHANECHOL    ,INDGREN ET AL HAVE SHOWN THAT AUTONOMIC NERVE DYSFUNCTION IS FREQUENTLY 4ABLE ))) "ASAL AND POSTPRANDIAL INTEGRATED PLASMA CONCENTRATIONS OF 00 ##+ AND 099 IN PATIENTS WITH SMALL AND LARGE BOWEL #ROHN DISEASE PATIENTS AFTER ILEOCECAL RESECTION AND HEALTHY CONTROLS

#ONTROLS

.   )LEAL #$

.   #OLONIC #$

.   )LEOCECAL RESECTION

.  

&ASTING 00 P-            

&ASTING ##+ P-            

&ASTING 099 P-            

!5# 00 P- MIN            

!5# ##+ P- MIN            

!5# 099 P- MIN            

0
 COMPARED TO PATIENTS WITH ILEAL #ROHN DISEASE AND TO CONTROLS

&IG  "ASAL AND POSTPRANDIAL PLASMA ##+ LEVELS P- MEAN

 STANDARD ERROR OF THE MEAN IN PATIENTS WITH #ROHN DISEASE OF THE ILEUM CLOSED TRIANGLES  OF THE COLON BIG SQUARES  IN PATIENTS AFTER ILEOCECAL RESECTION OPEN TRIANGLES AND HEALTHY CONTROLS SMALL SQUARES  0
 COMPARED TO PATIENTS WITH ILEAL #ROHN DISEASE AND CONTROLS

157

PRESENT IN PATIENTS WITH #ROHN DISEASE ESPECIALLY VAGUS DYSFUNCTION   "ASED ON THE RESULTS OF THESE STUDIES THEORETICALLY THE GALLBLADDER VOLUME SHOULD BE INCREASED IN PATIENTS WITH #ROHN DISEASE COMPARED TO CONTROLS (OWEVER THE lNDING OF A SMALLER FASTING GALLBLADDER VOLUME IN PATIENTS WITH LARGE BOWEL DISEASE AND AFTER ILEOCECAL RESECTION DOES NOT SUPPORT THE HYPOTHESIS OF AUTONOMIC DYSFUNCTION AS A FACTOR ACCOUNTING FOR THE SMALLER FASTING GALLBLADDER VOLUME

)N CONTRAST TO FASTING GALLBLADDER VOLUME NO SIGNIlCANT DIFFERENCE WAS FOUND IN POSTPRANDIAL GALLBLADDER EMPTYING BETWEEN PATIENTS WITH COLONIC DISEASE OR AFTER ILEOCECAL RESECTION COMPARED TO PATIENTS WITH SMALL BOWEL DISEASE AND CONTROLS !LTHOUGH SEVERAL STUDIES ON POSTPRANDIAL GALLBLADDER EMPTYING IN PATIENTS WITH #ROHN DISEASE HAVE BEEN PER FORMED NO CONSISTENT RESULTS HAVE BEEN OBTAINED n  -URRAY ET AL DOCUMENTED THAT GALLBLADDER EMPTYING IN RESPONSE TO A FATTY MEAL IS IMPAIRED IN PATIENTS WITH #ROHN DISEASE 4HE MOST PRONOUNCED IMPAIRMENT HAS BEEN OBSERVED IN PATIENTS WITH BOTH LARGE AND SMALL BOWEL DISEASE OR AFTER A PREVIOUS RESECTION   #ONSISTENT WITH THE RESULTS OF -URRAY ET AL $AMIAO ET AL HAVE SHOWN THAT GALLBLADDER EMPTYING IN RESPONSE TO A SOLID MEAL IS SIGNIlCANTLY REDUCED IN PATIENTS WITH #ROHN DISEASE AN ABNORMALITY WHICH IS NOT INmUENCED BY GASTRIC EMPTYING   5NFORTUNATELY DIFFERENCES IN GALLBLAD DER EMPTYING RELATED TO THE LOCALIZATION OF THE DISEASE OR AFTER RESECTION WERE NOT ANALYSED IN THE LATTER STUDY /N THE OTHER HAND -AURER ET AL FOUND NO EVIDENCE FOR ABNORMAL POSTPRANDIAL GALLBLADDER EMPTYING IN A GROUP OF  #ROHN DISEASE PATIENTS WITH SMALL ANDOR LARGE BOWEL DISEASE OR AFTER PREVIOUS RESECTION   4HE DISCREPANCY IN RESULTS BETWEEN THESE STUDIES COULD BE RELATED TO DIFFERENCES IN THE COMPOSI TION OF THE TEST MEALS AND DIFFERENCES IN PATIENT POPULATION )T HAS PREVIOUSLY BEEN SHOWN THAT THE PATTERN AND MAGNITUDE OF POSTPRANDIAL GALLBLADDER EMPTYING ARE DETERMINED BY THE TYPE COMPOSITION AND CALORIC VALUE OF THE MEAL   $IFFERENCES IN PATIENT POPULATION DUE TO THE HETEROGENEOUS NATURE OF #ROHN DISEASE WITH RESPECT TO DISEASE DURATION AND LOCALIZATION BOWEL RESECTION AND THE USE OF MEDICATION ARE PROBABLY THE MOST IMPORTANT FACTORS CONTRIBUTING TO THE DIFFERENT RESULTS FOUND BETWEEN THE STUDIES )N THE PRESENT STUDY WE HAVE MEASURED GALLBLADDER VOLUME IN PATIENTS WITH INACTIVE #ROHN DISEASE AND DATA WERE ANALYSED ACCORDING TO DISEASE LOCALIZATION AND BOWEL RESECTION

3INCE NO DIFFERENCES WERE FOUND IN POSTPRANDIAL GALLBLADDER EMPTYING AND RESIDUAL VOLUME QUESTIONS MUST BE RAISED CONCERNING THE ROLE OF GALLBLADDER MOTILITY IN THE FORMATION OF GALLSTONES IN PATIENTS WITH #ROHN DISEASE 2ESIDUAL VOLUME AND FRACTIONAL EMPTYING HAVE BEEN DOCUMENTED TO BE THE MOST IMPORTANT FACTORS PROMOTING STASIS AND GALLSTONE FORMATION

  )T IS NOT KNOWN WHETHER SMALLER FASTING GALLBLADDER VOLUMES ARE RELEVANT FOR GALLSTONE FORMATION )NSTEAD THERE IS EVIDENCE SUGGESTING THAT PATIENTS WITH CHOLESTEROL GALLSTONES ARE CHARACTERIZED BY ENLARGED FASTING GALLBLADDER VOLUMES

  'IVEN THE HIGHER PREVALENCE OF GALLSTONES IN PATIENT WITH

#ROHN ILEITIS OR AFTER ILEOCECAL RESECTION IT IS OBVIOUS THAT

OTHER PATHOGENETIC FACTORS FOR GALLSTONE FORMATION MUST BE INVOLVED %XCESS OF BILIARY CHOLESTEROL IN RELATION TO PHOS PHOLIPIDS AND BILE ACIDS DUE TO BILE ACID MALABSORPTION IN PATIENTS WITH #ROHN DISEASE IN THE ILEUM OR AFTER ILEOCECAL RESECTION HAS BEEN REPORTED    (OWEVER RECENT STUDIES HAVE DOCUMENTED THAT CHOLESTEROL SATURATION OF BILE IS NOT INCREASED IN PATIENTS WITH #ROHN DISEASE AFTER ILEOCECAL RESECTION    .OT ONLY THE SIZE BUT ALSO THE COMPOSITION OF THE BILE ACID POOL IS RELEVANT FOR CHOLESTEROL GALLSTONE FORMATION 4HE SECONDARY BILE ACID DEOXYCHOLIC ACID STIMU LATES CHOLESTEROL SECRETION TO A LARGER EXTENT THAN PRIMARY BILE ACIDS   4HE BILIARY CONCENTRATION OF DEOXYCHOLIC ACID IS DECREASED IN PATIENTS WITH #ROHN COLITIS WHO HAVE A LOW INCIDENCE OF GALLSTONES    $ATA ON THE CONCENTRATION OF DEOXYCHOLIC ACID IN PATIENTS WITH #ROHN DISEASE OF THE ILEUM OR AFTER ILEOCECAL RESECTION ARE LESS CONSISTENT     ,APIDUS  %INARSSON HAVE FOUND THAT IN ADDITION TO THE DECREASED CONCENTRATION OF DEOXYCHOLIC ACID IN DUODENAL BILE THE AMOUNT OF URSODEOXYCHOLIC ACID IS INCREASED IN PATIENTS AFTER ILEOCECAL RESECTION   )T IS ALSO POSSIBLE THAT PIGMENT RATHER THAN CHOLESTEROL GALLSTONES ARE PRESENT IN PATIENTS WITH ILEAL DYSFUNCTION OR AFTER ILEAL RESECTION )T HAS BEEN SHOWN IN ANIMAL MODELS THAT AFTER ILEAL RESECTION ESPECIALLY PIGMENT GALLSTONES ARE FORMED   -ORE RECENTLY "RINK ET AL HAVE SHOWN THAT GALLBLADDER BILE OF PATIENTS WITH ILEAL #ROHN DISEASE IS SATURATED WITH UNCONJUGATED BILIRUBIN  

)N CONCLUSION PATIENTS WITH INACTIVE #ROHN DISEASE OF THE LARGE BOWEL AND PATIENTS AFTER ILEOCECAL RESECTION HAVE SMALLER FASTING GALLBLADDER VOLUMES AND INCREASED BASAL PLASMA ##+

LEVELS 'ALLBLADDER MOTILITY AND SUBSEQUENT HORMONE RELEASE IN RESPONSE TO A MEAL ARE ON THE OTHER HAND NOT AFFECTED IN PATIENTS WITH INACTIVE #ROHN DISEASE IRRESPECTIVE OF DISEASE LOCALIZATION AND PREVIOUS BOWEL RESECTION 'ALLBLADDER

DYS MOTILITY DOES NOT SEEM TO CONTRIBUTE TO GALLSTONE FORMATION IN PATIENTS WITH #ROHN DISEASE

2EFERENCES

 #OHEN 3 +APLAN - 'OTTLEIB , 0ATTERSON * ,IVER DISEASE AND GALLSTONES IN REGIONAL ENTERITIS 'ASTROENTEROLOGY n



 "AKER !, +APLAN - .ORTON !0 0ATTERSON * 'ALLSTONES IN INmAMMATORY BOWEL DISEASE !M * $IG $IS n

 7HORWELL *0 (AWKINS 2 $EWBURY + 7RIGHT 2 5LTRASOUND SURVEY OF GALLSTONES AND OTHER HEPATOBILIARY DISORDERS IN PATIENTS WITH #ROHNS DISEASE $IG $IS 3CI n

 ,ORUSSO $ 3ILVANA , -OSSA ! -ISCIAGNA ' 'UERRA 6

#HOLELITHIASIS IN INmAMMATORY BOWEL DISEASE $IS #OLON 2ECT

n

 ,APIDUS ! "ANGSTAD - !ƒ STRO‚M - -UHRBECK / 4HE PREVALENCE OF GALLSTONE DISEASE IN A DElNED COHORT OF PATIENTS WITH #ROHNS DISEASE !M * 'ASTROENTEROL n

 0AUMGARTNER ' 3AUERBRUCH 4 'ALLSTONES PATHOGENESIS ,ANCET

n

 ,EVY 0& 3MITH "& ,A-ONT *4 (UMAN GALLBLADDER MUCINE ACCELERATES NUCLEATION OF CHOLESTEROL IN ARTIlCIAL BILE 'ASTRO ENTEROLOGY n

 $OWLING 2( "ELL '$ 7HITE * ,ITHOGENIC BILE INPATIENTS WITH ILEAL DYSFUNCTION 'UT n

 -ARKS *7 #ONLEY $2 #APRETTA 4, "ONORRIS '' #HUNNG !

158

#OYNE -* ET AL 'ALLSTONE PREVALENCE AND BILIARY LIPID COMPOSITION IN INmAMMATORY BOWEL DISEASE $IG $IS 3CI 

n

 -URRAY &% -C.ICHOLAS - 3TACK 7 /$ONOGHUE $0

)MPAIRED FATTY MEAL STIMULATED GALLBLADDER CONTRACTILITY IN PATIENTS WITH #ROHNS DISEASE #LIN 3CI n

 !NNESE 6 6ANTRAPPEN ' 'ALLSTONES IN #ROHNS DISEASE OTHER HYPOTHESIS 'UT 

 -AURER 0 (AAG + 2OTH - +UDER # 3CHO‚LMERICH * .O EVIDENCE FOR ABNORMAL GALLBLADDER EMPTYING IN #ROHNS DISEASE

(EPATOGASTROENTEROLOGY n

 $AMIAO !/-# 3IPAHI !- 6EZOZZO $0 'ONCALVES 0, &UKUI 0 ,AUDANNA !! 'ALLBLADDER HYPOKINESIA IN #ROHNS DISEASE

$IGESTION n

 %VERSON '4 "RAVERMAN $: *OHNSON -, +ERN & *R ! CRITICAL EVALUATION OF REAL TIME ULTRASONOGRAPHY FOR THE STUDY OF GALL BLADDER VOLUME AND CONTRACTION 'ASTROENTEROLOGY n

 (OPMAN 70- "ROUWER 7&- 2OSENBUSCH ' *ANSEN *"-*

,AMERS #"(7 ! COMPUTERIZED METHOD FOR RAPID QUANTIlCATION OF GALLBLADDER VOLUME FROM REAL TIME SONOGRAMS 2ADIOLOGY

n

 *ANSEN *"-* ,AMERS #"(7 2ADIOIMMUNOASSAY OF CHOLECYS TOKININ IN HUMAN TISSUE AND PLASMA #LIN #HIM !CTA 

n

 ,AMERS #"(7 $IEMEL #- 6AN ,EER % 6AN ,EUSEN 2 0EETOOM ** -ECHANISM OF ELEVATED SERUM PANCREATIC POLYPEP TIDE CONCENTRATIONS IN CHRONIC RENAL FAILURE * #LIN %NDOCRINOL -ETAB n

 -ASCLEE !! *ANSEN *" $RIESSEN 7- 'EUSKENS ,- ,AMERS

#" 0LASMA CHOLECYSTOKININ AND GALLBLADDER RESPONSES TO INTRA DUODENAL FAT IN GALLSTONE PATIENTS $IG $IS 3CI   n

 (OPMAN 70- +ERSTENS 0*3- *ANSEN *"-* 2OSENBUSCH ' ,AMERS #"(7 %FFECT OF GRADED PHYSIOLOGIC DOSES OF CHOLECYSTOKININ ON GALLBLADDER CONTRACTION MEASURED BY ULTRA SONOGRAPHY $ETERMINATION OF THRESHOLD DOSEnRESPONSE RELATION SHIPS AND COMPARISON WITH INTRADUODENAL BILIRUBIN OUTPUT

'ASTROENTEROLOGY n

 *EBBINK -#7 -ASCLEE !!- VAN DER +LEIJ &' 3CHIPPER * 2OVATI ,# *ANSEN *" ET AL %FFECT OF LOXIGLUMIDE AND ATROPINE ON ERYTHROMYCINE INDUCED REDUCTION IN GALLBLADDER VOLUME IN HUMAN SUBJECTS (EPATOLOGY  n

 3ALEMANS *- 4HIRISTER 07 (OPMAN 70 +UIJPERS (#

2OSENBUSCH ' .AGANGAST &- ET AL 0LASMA CHOLECYSTOKININ LEVELS AND GALLBLADDER VOLUMES AFTER PROCTOCOLECTOMY WITH ILEAL POUCH ANAL ANASTOMOSIS 3URGERY n

 0IRONI , 3TANGHELLINI 6 -IGLIOLI - ET AL &AT INDUCED ILEAL BRAKE IN HUMANS A DOSE DEPENDENT PHENOMENON CORRELATED TO THE PLASMA LEVELS OF PEPTIDE 99 'ASTROENTEROLOGY 

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 !DRIAN 4% &ERRI ', "ACARESE (AMILTON !* &UESSL (3 0OLAK

*- "LOOM 32 (UMAN DISTRIBUTION AND RELEASE OF A PUTATIVE NEW GUT HORMONE PEPTIDE 99 'ASTROENTEROLOGY 

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 #ONTER 2, 2OSLYN ** 4AYLOR ), %FFECTS OF PEPTIDE 99 ON GALLBLADDER MOTILITY !M * 0HYSIOL 'n'

 &ISHER 23 2OCK % -ALMUD ,3 #HOLINERGIC EFFECTS ON GALLBLADDER EMPTYING IN HUMANS 'ASTROENTEROLOGY 

n

 (ANSE 7% -AURER ( (ABERLAND ( 4HE EFFECT OF SHAM FEEDING ON GALLBLADDER VOLUME AND CIRCULATION OF BILE ACIDS (EPATO GASTROENTEROLOGY n

 &ISHER 23 2OCK % -ALMUD ,3 'ALLBLADDER EMPTYING IN RESPONSE TO SHAM FEEDING IN HUMANS 'ASTROENTEROLOGY 

n

 ,INDGREN 3 ,ILJA " 2OSEN ) 3UNDKVIST ' $ISTURBED AUTONOMIC NERVE FUNCTION IN PATIENTS WITH #ROHNS DISEASE 3CAND * 'ASTROENTEROL n

 &ROEHLICH & 'ONVERS ** &RIED - 2OLE OF NUTRIENT FAT AND CHOLECYSTOKININ IN REGULATION OF GALLBLADDER EMPTYING IN MAN

$IG $IS 3CI n

 %VERSON '4 'ALLBLADDER FUNCTION IN GALLSTONE DISEASE 'ASTRO ENTEROL #LIN . !M n

 &ESTI $ &RABBONI 2 "AZZOLI & 3ANGERMANO ! 2ONCHI - 2OSSI , ET AL 'ALLBLADDER MOTILITY IN CHOLESTEROL GALLSTONE DISEASE

'ASTROENTEROLOGY n

 ,APIDUS ! %INARSSON + %FFECTS OF ILEAL RESECTION ON BILIARY LIPIDS AND BILE ACID COMPOSITION IN PATIENTS WITH #ROHNS DISEASE 'UT n

 ,APIDUS ! %INARSSON # "ILE COMPOSITION IN PATIENTS WITH ILEAL RESECTION DUE TO #ROHNS DISEASE )NmAMM "OWEL $IS 

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 #ARULLI .0 ,ORIA 0 "ERTOLOTTI - 0ONZ DE ,EON - -ENOZZI $ -EDICI ' ET AL %FFECTS OF ACUTE CHANGES OF BILE ACID POOL COMPOSITION OF BILIARY LIPID SECRETION * #LIN )NVEST 

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 2UTGEERTS 0 'HOOS 9 6ANTRAPPEN ' "ILE ACID STUDIES IN PATIENTS WITH #ROHNS COLITIS 'UT n

 2UTGEERTS 0 'HOOS 9 6ANTRAPPEN ' +INETICS OF PRIMARY BILE ACIDS IN PATIENTS WITH NON OPERATED #ROHNS DISEASE %UR * #LIN )NVEST n

 +RUIS 7 +ALEK ($ 3TELLAARD & 0AUMGARTNER ' !LTERED FAECAL BILE ACID PATTERN IN PATIENTS WITH INmAMMATORY BOWEL DISEASE

$IGESTION n

 0ITT (! ,EWENSKI -! -ULLER %, 0ORTER &RINK 6 $EN "ESTEN , )LEAL RESECTION INDUCED GALLSTONES ALTERED BILIRUBIN OR CHOLESTEROL METABOLISM 3URGERY n

 "RINK -! 3LORS *2- +EULEMANS 9# -OK +3 DE 7AART $2

#AREY -# ET AL %NTEROHEPATIC CYCLING OF BILIRUBIN A PUTATIVE MECHANISM FOR PIGMENT GALLSTONE FORMATION IN PATIENTS WITH ILEAL

#ROHNS DISEASE 'ASTROENTEROLOGY  n