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Dysfunction of gallbladder motility in patients with anorexia nervosa
April 1995
Biliary Disorders A439
• EFFECT OF CHOLESTYRAMINE ON PANCREATIC ENZYME SECRETION, GALLBLADDER MOTILITY AND. PLASMA CHOLECYSTOKININ RELEASE IN RESPONSE TO AN INTRADUODENAL AMINO ACID MEAL. P.W.L. Thimister, A. Loualidi, W.P.M. Hopman, G. Rosenbusch', J.L. Willems 2 and J.B.M.J. Jansen. Depts. of Gastroenterology, Radiology] and Clinical Chemistry", University Hospital Nijmegen, The Netherlands. Cholestyramine enhances gallbladder emptying and plasma cholecystokinin (CCK) responses to oral ingestion of a mixed meal, most probably by sequestration of bile acids in the lumen of the small intestine. Since this effect may be mediated by alterations of gastric emptying or intraduodenal digestion of fatty nutrients, we have determined if cholestyramine also augments pancreatic enzyme secretion, gallbladder motility and plasma CCK when an amino acid meal is administered intraduodenally. Methods: 7 healthy subjects (4M,3F;23.3± 1.1 yrs.) were studied on different occasions. After an overnight fast 2 tests where performed in random order each lasting for three hours. In test 1 saline was continuously perfused intraduodenally for three hours (300 mL/h). During the last test hour 15 g of an amino acid solution (in the same molecular composition as albumin) was added to the saline. Test 2 was performed accord!ng to the same protocol as test 1 but 12 g of cholestyramine was added to the saline during the last two test hours. At regular intervals plasma CCK levels (R!A), amylase output (duodenal spot sampling with PEG-4000 as a recovery marker) and gallbladder volume (ultrasonography) were measured. Results: Cholestyramine did not influence basal plasma CCK levels (-6.1+_7.6 pM,,60min vs -8.9_+6.3 pM,,60min;NS) nor basal amylase output (4.0_+ 1.3 kU /h vs 2.8_+0.9 kU/h;NS), while it induced a small but significant gallbladder contraction from -12l± 121%°60rain in test' 1 to 748±352%"60minqn test 2 (p<0.05). During intraduodenal administration of the amino acid~meal, cholestyramine enhanced incremental plasma CCK from 35.5± 11.5 pMo60min in test 1 to 139.2_+24.7 pM°60min in test 2 (p<0.005), incremental amylase output from 2:4±0.7 kU/h in test 1 to 5.7±0.7 kU/h in test 2 (p<0.05) and integrated gallbladder contraction from 1948+235%°60min in test 1 to 2840±lg9%'60min in test 2 (p<0.05). Conclusions: Cholestyramine also enhances pancreatico-biliary and plasma CCK responses to an intraduodenal amino acid meal, suggesting that the mechanism is not dependent on gastric emptying or the presence of fatty nutrients in the gut.
• EFFECT OF LOPERAM[DE ON BASAL AND AMINO ACID STIMULATED PLASMA CHOLECYSTOKININ AND GALLBLADDER EMPTYING IN HUMANS. P.W.L. Thimister, W.P.M. Hopman, G. Rosenbusch~, J.L. Willems 2, R. Woestenborghs3 and J.B.M.J. Jansen. Depts. of Gastroenterology, Radiology~ and Clinical Chemistry2, University Hospital Nijmegen, The Netherlands and Drug, Metabolism and Pharmacokinetics3, Janssen Pharmaceutica, Belgium. Loperamide is a peripherally acting opiate receptor agonist with antidiarrhoeal action. These receptors have been located in the duodenal mucosa, cystic duct and gallbladder. To determine whether opiate receptors modulate gallbladder motility and plasma cholecystokinin (CCK) release, we have studied the effect of loperamide on these functions under basal and postprandial conditions. Methods: 2 studies were performed in 7 healthy subjects (2F,5M;23.1 ± 1.1 yrs.). After an overnight fast saline was continuously perfused intraduodenally (i.d.) for three hours (300 mL/h) in test 1. During the last test hour 6.9 g of an amino acid (AA) solution, containing valine, methionine, tryptophan and phenylalanine was also given i.d. Test 2 was performed on a separate occasion according to the same protocol as test 1. However, 13 and 4 hours prior to the start of the AA perfusion, 8 mg of loperamide was given orally. Plasma CCK and loperamide levels (RIA), bilirubin output (duodenal spot sampIing using PEG-4000 as a recovery marker) and gallbladder volume (ultrasonography) were measured at regular intervals. Results: Plasma levels of Ioperamide at the start of AA perfusion were 2.5±0.3 ng/mL in the Ioperamide study. Loperamide increased basal gallbladder volume from 29±4 mL to 40_+5 mL (p<0.001) and completely abolished basal bilirubin output into the duodenum from 17.7±3.7 to 0.0±0.0 amol/h (p<0.005). After pretreatment with loperamide both integrated gallbladder contraction and incremental bilirubin output in response to the AA meal were markedly inhibited from 488_+78 mL.60min and 26.2+7.6 #mol/60min in test 1 to 219_+69 mL°60min (p<0.05) and 19.4+_6.1 Fmol/60min (p<0.05) respectively in test 2. Loperamide did not affect basal plasma CCK (3.2+_0.2 pM), but it significantly enhanced incremental plasma CCK from 22.5±8.6 pM',30min in test 1 to 63.7_+11.7 pM"30min in test 2 (p<0.01) during the last 30 rain of AA perfusion. Conclusions: Loperamide inhibits basal and amino acid stimulated gallbladder motility and intraduodenal bilirubin output, despite an enhanced amino acid stimulated CCK release. Therefore peripheral opiate receptors can modulate these functions in man.
IS HEPATOCYTE EXTRACTION FRACTION (HEF) OF ANY VALUE IN EVALUATION OF NEONATAL CHOLESTASlS (NC)? V. Tolia, D. Tabbussum, P. Simpson, E. Patterson, S. Kottamasu, Departments of Pediatrics and Radiology, Children's Hospital of Michigan, (CHM) Detroit. Hepetobiliary Scintigraphy (HBS) is routinely used in evaluation of NC. HBS determifies biliery petency by detecting radioactivity in bowel on direct imaging and/or on duodenal and gastric aspirates and HEF is calculated by deconvolutional analysis. Normal values for HEF ere > 80%. It is believed that HEF may predict liver function status and has a directly correlation to the degree of hepatic dysfunction; i.e., low value of HEF is seen with > severe liver disease. We did a retrospective analysis of 68 HBS results in patients with NC during last 6 years HEF was available in 57 patients with a median value of 25% (range 3.3 - 100%). We failed to find any relationship between HEF and levels of total and direct bilirubin, albumin, ALP in serum and PT by exploratory data analysis (r - very small, p >0.2). We then compared HEF values in different causes of NC: extra-hepatic biliary etresia (EHBA), Neonatal Hepatitis (NH) and a miscellaneous (MISC) category, consisting of ~1 -AT deficiency, ischemic hepatitis, paucity of bile ducts and others. Their outcomes were assessed as resolution, continuing disease, transplantation and death shown in the boxplot below and found no predictive correlation with HEF. We conclude that HEF is of no value in assessing synthetic liver function, specific diagnoses and outcome in patients with NC.
D Y S F U N C T I O N O F G A L L B L A D D E R M O T I L I T Y IN P A T I E N T S W I T H A N O R E X I A N E R V O S A . A. Uehara, M. Moriya, T. Kubota, K. Kubo, T. Nozu, F. Shaku, Y. Watanabe, E. Shoji, S.B. Santos, K. Harada, Y. Kohgo. Dept. of Internal Medicine (IIl), Asahikawa Medical College, Asahikawa, Hokkaldo 078, Japan Patients with anorexia nervosa (AN) frequently complain of various abdominal symptoms such as epigastric discomfort, bloating and constipation suggestive of abnormal gastrointestinal motility or transit. In fact, there is a well-documented delay in gastric emptying, colonic and small bowel transit or whole-gut transit in AN patients. Although it is speculated that some of these digestive symptoms are possibly attributable to gallbladder dysmotility, there is little information on gallbladder motility in AN patients. In the present study, we examined gallbladder contractility in response to cholecystokinin (CCK) in 7 AN patients (all females, 20.2 -+ 2.4 yrs, mean _+SEM) and 10 age- and sex-matched hea!thy controls (21.5 -+ 2.1 yrs). The 7 patients were admitted to our hospital without prior medical treatment elsewhere. Contractile response of the gallbladder was assessed using a real-time ultrasonography (Hitachi EUB410, Tokyo, Japan) with an application frequency of 3.5 M Hi! The gallbladder was visualized through a right subcostal or intercostal space by the hand-held transducer being angled to obtain images showing the largest longitudinal diameter. Tracing the gallbladder wall circularly enabled the calculation of the gallbladder area by this unit. The gallbladder area was measured at 0, 5, 10, 15, 20, 25, 30, 45, 60, 90, 120 min after the intramuscular bolus injection of the synthetic CCK analogue caerulein (0.2 ~tg/kg). Contractile response was expressed as percentage of the resting gallbladder area (%). The CCK-induced maximal contraction of the gallbladder in the AN group was significantly enhanced than that in the control group (21.5 -+ 5.8 % vs. 35.6 -+ 6.8 %, p < 0.01, mean + SEM). Time to reach the maximal contraction was significantly delayed in the AN group, as compared with the control group (40.2 _+ 19.5 min vs. 28.6 + 5.9 min, p < 0.05, mean + SEM). Although gallbladder refilling time was 75.6 + 19.2 rain in the control group (mean _+ SEM), the size of the gallbladder did not return to the pre-stimulated level within 120 rain in all AN patients. These alterations of gallbladder contractile parameters in the AN group tended to normalize after successful treatment. These results clearly demonstrate that AN patients develop gallbladder dyskinesia, thereby suggesting that gallbladder dysfunction may contribute to the pathogenesis of some abdominal symptoms in AN patients. Possible underlying mechanisms for this gallbladder motor dysfunction include changes in CCK receptors on the gallbladder muscle, functional impairment of the gallbladder" muscle itself or influences from the central nervous system through the vagal nerve innervating the gallbladder.
Biliary Disorders A439
• EFFECT OF CHOLESTYRAMINE ON PANCREATIC ENZYME SECRETION, GALLBLADDER MOTILITY AND. PLASMA CHOLECYSTOKININ RELEASE IN RESPONSE TO AN INTRADUODENAL AMINO ACID MEAL. P.W.L. Thimister, A. Loualidi, W.P.M. Hopman, G. Rosenbusch', J.L. Willems 2 and J.B.M.J. Jansen. Depts. of Gastroenterology, Radiology] and Clinical Chemistry", University Hospital Nijmegen, The Netherlands. Cholestyramine enhances gallbladder emptying and plasma cholecystokinin (CCK) responses to oral ingestion of a mixed meal, most probably by sequestration of bile acids in the lumen of the small intestine. Since this effect may be mediated by alterations of gastric emptying or intraduodenal digestion of fatty nutrients, we have determined if cholestyramine also augments pancreatic enzyme secretion, gallbladder motility and plasma CCK when an amino acid meal is administered intraduodenally. Methods: 7 healthy subjects (4M,3F;23.3± 1.1 yrs.) were studied on different occasions. After an overnight fast 2 tests where performed in random order each lasting for three hours. In test 1 saline was continuously perfused intraduodenally for three hours (300 mL/h). During the last test hour 15 g of an amino acid solution (in the same molecular composition as albumin) was added to the saline. Test 2 was performed accord!ng to the same protocol as test 1 but 12 g of cholestyramine was added to the saline during the last two test hours. At regular intervals plasma CCK levels (R!A), amylase output (duodenal spot sampling with PEG-4000 as a recovery marker) and gallbladder volume (ultrasonography) were measured. Results: Cholestyramine did not influence basal plasma CCK levels (-6.1+_7.6 pM,,60min vs -8.9_+6.3 pM,,60min;NS) nor basal amylase output (4.0_+ 1.3 kU /h vs 2.8_+0.9 kU/h;NS), while it induced a small but significant gallbladder contraction from -12l± 121%°60rain in test' 1 to 748±352%"60minqn test 2 (p<0.05). During intraduodenal administration of the amino acid~meal, cholestyramine enhanced incremental plasma CCK from 35.5± 11.5 pMo60min in test 1 to 139.2_+24.7 pM°60min in test 2 (p<0.005), incremental amylase output from 2:4±0.7 kU/h in test 1 to 5.7±0.7 kU/h in test 2 (p<0.05) and integrated gallbladder contraction from 1948+235%°60min in test 1 to 2840±lg9%'60min in test 2 (p<0.05). Conclusions: Cholestyramine also enhances pancreatico-biliary and plasma CCK responses to an intraduodenal amino acid meal, suggesting that the mechanism is not dependent on gastric emptying or the presence of fatty nutrients in the gut.
• EFFECT OF LOPERAM[DE ON BASAL AND AMINO ACID STIMULATED PLASMA CHOLECYSTOKININ AND GALLBLADDER EMPTYING IN HUMANS. P.W.L. Thimister, W.P.M. Hopman, G. Rosenbusch~, J.L. Willems 2, R. Woestenborghs3 and J.B.M.J. Jansen. Depts. of Gastroenterology, Radiology~ and Clinical Chemistry2, University Hospital Nijmegen, The Netherlands and Drug, Metabolism and Pharmacokinetics3, Janssen Pharmaceutica, Belgium. Loperamide is a peripherally acting opiate receptor agonist with antidiarrhoeal action. These receptors have been located in the duodenal mucosa, cystic duct and gallbladder. To determine whether opiate receptors modulate gallbladder motility and plasma cholecystokinin (CCK) release, we have studied the effect of loperamide on these functions under basal and postprandial conditions. Methods: 2 studies were performed in 7 healthy subjects (2F,5M;23.1 ± 1.1 yrs.). After an overnight fast saline was continuously perfused intraduodenally (i.d.) for three hours (300 mL/h) in test 1. During the last test hour 6.9 g of an amino acid (AA) solution, containing valine, methionine, tryptophan and phenylalanine was also given i.d. Test 2 was performed on a separate occasion according to the same protocol as test 1. However, 13 and 4 hours prior to the start of the AA perfusion, 8 mg of loperamide was given orally. Plasma CCK and loperamide levels (RIA), bilirubin output (duodenal spot sampIing using PEG-4000 as a recovery marker) and gallbladder volume (ultrasonography) were measured at regular intervals. Results: Plasma levels of Ioperamide at the start of AA perfusion were 2.5±0.3 ng/mL in the Ioperamide study. Loperamide increased basal gallbladder volume from 29±4 mL to 40_+5 mL (p<0.001) and completely abolished basal bilirubin output into the duodenum from 17.7±3.7 to 0.0±0.0 amol/h (p<0.005). After pretreatment with loperamide both integrated gallbladder contraction and incremental bilirubin output in response to the AA meal were markedly inhibited from 488_+78 mL.60min and 26.2+7.6 #mol/60min in test 1 to 219_+69 mL°60min (p<0.05) and 19.4+_6.1 Fmol/60min (p<0.05) respectively in test 2. Loperamide did not affect basal plasma CCK (3.2+_0.2 pM), but it significantly enhanced incremental plasma CCK from 22.5±8.6 pM',30min in test 1 to 63.7_+11.7 pM"30min in test 2 (p<0.01) during the last 30 rain of AA perfusion. Conclusions: Loperamide inhibits basal and amino acid stimulated gallbladder motility and intraduodenal bilirubin output, despite an enhanced amino acid stimulated CCK release. Therefore peripheral opiate receptors can modulate these functions in man.
IS HEPATOCYTE EXTRACTION FRACTION (HEF) OF ANY VALUE IN EVALUATION OF NEONATAL CHOLESTASlS (NC)? V. Tolia, D. Tabbussum, P. Simpson, E. Patterson, S. Kottamasu, Departments of Pediatrics and Radiology, Children's Hospital of Michigan, (CHM) Detroit. Hepetobiliary Scintigraphy (HBS) is routinely used in evaluation of NC. HBS determifies biliery petency by detecting radioactivity in bowel on direct imaging and/or on duodenal and gastric aspirates and HEF is calculated by deconvolutional analysis. Normal values for HEF ere > 80%. It is believed that HEF may predict liver function status and has a directly correlation to the degree of hepatic dysfunction; i.e., low value of HEF is seen with > severe liver disease. We did a retrospective analysis of 68 HBS results in patients with NC during last 6 years HEF was available in 57 patients with a median value of 25% (range 3.3 - 100%). We failed to find any relationship between HEF and levels of total and direct bilirubin, albumin, ALP in serum and PT by exploratory data analysis (r - very small, p >0.2). We then compared HEF values in different causes of NC: extra-hepatic biliary etresia (EHBA), Neonatal Hepatitis (NH) and a miscellaneous (MISC) category, consisting of ~1 -AT deficiency, ischemic hepatitis, paucity of bile ducts and others. Their outcomes were assessed as resolution, continuing disease, transplantation and death shown in the boxplot below and found no predictive correlation with HEF. We conclude that HEF is of no value in assessing synthetic liver function, specific diagnoses and outcome in patients with NC.
D Y S F U N C T I O N O F G A L L B L A D D E R M O T I L I T Y IN P A T I E N T S W I T H A N O R E X I A N E R V O S A . A. Uehara, M. Moriya, T. Kubota, K. Kubo, T. Nozu, F. Shaku, Y. Watanabe, E. Shoji, S.B. Santos, K. Harada, Y. Kohgo. Dept. of Internal Medicine (IIl), Asahikawa Medical College, Asahikawa, Hokkaldo 078, Japan Patients with anorexia nervosa (AN) frequently complain of various abdominal symptoms such as epigastric discomfort, bloating and constipation suggestive of abnormal gastrointestinal motility or transit. In fact, there is a well-documented delay in gastric emptying, colonic and small bowel transit or whole-gut transit in AN patients. Although it is speculated that some of these digestive symptoms are possibly attributable to gallbladder dysmotility, there is little information on gallbladder motility in AN patients. In the present study, we examined gallbladder contractility in response to cholecystokinin (CCK) in 7 AN patients (all females, 20.2 -+ 2.4 yrs, mean _+SEM) and 10 age- and sex-matched hea!thy controls (21.5 -+ 2.1 yrs). The 7 patients were admitted to our hospital without prior medical treatment elsewhere. Contractile response of the gallbladder was assessed using a real-time ultrasonography (Hitachi EUB410, Tokyo, Japan) with an application frequency of 3.5 M Hi! The gallbladder was visualized through a right subcostal or intercostal space by the hand-held transducer being angled to obtain images showing the largest longitudinal diameter. Tracing the gallbladder wall circularly enabled the calculation of the gallbladder area by this unit. The gallbladder area was measured at 0, 5, 10, 15, 20, 25, 30, 45, 60, 90, 120 min after the intramuscular bolus injection of the synthetic CCK analogue caerulein (0.2 ~tg/kg). Contractile response was expressed as percentage of the resting gallbladder area (%). The CCK-induced maximal contraction of the gallbladder in the AN group was significantly enhanced than that in the control group (21.5 -+ 5.8 % vs. 35.6 -+ 6.8 %, p < 0.01, mean + SEM). Time to reach the maximal contraction was significantly delayed in the AN group, as compared with the control group (40.2 _+ 19.5 min vs. 28.6 + 5.9 min, p < 0.05, mean + SEM). Although gallbladder refilling time was 75.6 + 19.2 rain in the control group (mean _+ SEM), the size of the gallbladder did not return to the pre-stimulated level within 120 rain in all AN patients. These alterations of gallbladder contractile parameters in the AN group tended to normalize after successful treatment. These results clearly demonstrate that AN patients develop gallbladder dyskinesia, thereby suggesting that gallbladder dysfunction may contribute to the pathogenesis of some abdominal symptoms in AN patients. Possible underlying mechanisms for this gallbladder motor dysfunction include changes in CCK receptors on the gallbladder muscle, functional impairment of the gallbladder" muscle itself or influences from the central nervous system through the vagal nerve innervating the gallbladder.