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Gallbladder motility in obesity, diabetes mellitus and coeliac disease
Digestive and Liver Disease 35 (Suppl. 3) (2003) S12–S16 www.elsevier.com / locate / dld
Gallbladder motility in obesity, diabetes mellitus and coeliac disease M. Fraquelli, M. Pagliarulo, A. Colucci, S. Paggi, D. Conte* Chair of Gastroenterology, University of Milan, Milan, Italy
Abstract We reviewed data on gallbladder motility in obesity, diabetes and coeliac disease. In obesity, a condition characterised by increased risk of gallstone(s), decreased gallbladder motility has heterogeneously been reported as a consequence of the different type of meals used to induce gallbladder contraction, characteristics of the population studied, technique used, and proportion of patients with hyperinsulinaemia. Moreover, recent studies have evaluated the effect of dietary restriction on gallbladder motility in obese patients. A two- to three-fold increase in the risk of cholesterol gallstone(s) has been reported in diabetic patients, mainly in relation to obesity and hypertriglyceridaemia. Furthermore, decreased gallbladder motility has been described and attributed to other factors, including underlying autonomic neuropathy, reduced gallbladder sensitivity to cholecystokinin and / or reduced number of cholecystokinin receptors on the gallbladder wall. Impaired gallbladder motility has been reported also in patients with coeliac disease in relation to reduced secretion of enteric hormones and / or decreased gallbladder sensitivity to them. In particular, untreated coeliacs, when compared to controls, showed low postprandial cholecystokinin and increased fasting somatostatin levels. Interestingly, the correlation between fasting somatostatin levels and gallbladder size has clearly been confirmed in patients affected by somatostatinoma or treated with somatostatin or its analogues. Gallbladder motility can be affected by various clinical conditions, such as obesity, diabetes mellitus and coeliac disease. 2003 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Coeliac disease; Diabetes mellitus; Gallbladder motility; Obesity; Ultrasound
1. Obesity Obesity is a major risk factor for gallstone disease (GD) [1,2], bile super-saturation, related to the increased synthesis of cholesterol [3], being the main pathogenic factor for gallstone formation. Two other factors also play a relevant role, namely increase in fasting gallbladder (GB) volume and reduction in postprandial (P-P) GB motility. The former has been reported in a number of studies, most of which correlated with body weight, body mass index (BMI) and surface area [4,5], as well as with abdominal fat and impaired glucose tolerance, as in a metabolic syndrome characterised by central adiposity and hyperinsulinaemia [6]. Reduction in P-P GB emptying has been heterogeneously reported (Table 1), probably due to differences in the type of meal used to induce GB contraction, characteristics of the population studied (in terms of BMI, sex, etc.), and technique used to evaluate GB kinetics (i.e., scintigraphy
*Corresponding author. Tel.: 139-02-5503-3418; fax: 139-02-55033644. E-mail address: [email protected] (D. Conte).
or ultrasonography). Conflicting data may also be related to differences in the proportion of obese subjects with hyperinsulinaemia, which can decrease GB sensitivity to cholecystokinin (CCK) with a consequent reduction in GB contraction [7]. Particular interest has been shown in the effect of dietary restriction on obese patients. During rapid weight loss, a significant increase in gallstone disease (GD) has been reported repeatedly, with an overall frequency ranging from 11 to 36% [12]. The underlying pathogenic mechanisms are incompletely understood, but several factors have been considered, including an increase in cholesterol biliary output [13] and / or GB secretion of Table 1 P-P GB motility in obese subjects Author [Ref.]
Patients (n)
Meal type
Technique used
P-P GB a motility
Marzio [8] Acalovschi [9] Stone [10] Vezina [11]
21 44 7 18
Solid Solid Liquid Liquid
US US US Scintigraphy
↓ ND ND ↓
ND, no significant differences; US, ultrasound;↓, decreased. a Versus controls.
1590-8658 / 03 / $30 2003 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016 / S1590-8658(03)00087-2
M. Fraquelli et al. / Digestive and Liver Disease 35 ( Suppl. 3) (2003) S12 –S16
mucin and calcium, and a decrease in bile PGE2 and arachidonic acid levels [14,15]. A very low calorie diet also induces GB stasis, possibly as a consequence of reduced GB stimulation [12,16]. In this context, the most important factor is the actual intake of dietary fat, 10 g being the threshold amount necessary to induce efficient GB emptying [10]. This has been clearly shown by Gebhard et al. [17], who compared two different regimens of 520 kcal (with ,2 g of fat) and 900 kcal (with 10 g of fat). GD developed in 66% of patients in the first group, who also showed severely reduced GB emptying (to an average of 35%), whereas GD developed in none of the patients in the second group, who showed less reduction in GB emptying (to an average of 66%). This aspect was further investigated by Festi et al. [16], who used two isocaloric regimens of |550 kcal each, with different amount of fat (3 vs. 12.2 g / day); as expected, a significant proportion of patients on the low fat schedule developed GD (54% vs. no case in the other group) and showed a marked reduction of GB emptying (which was normal in the high fat group). In a recent study of Zapata et al. [18], incidence of GD and pattern of GB emptying were similar in 12 obese subjects and 12 healthy females given a diet of 800–1200 kcal / day with 26 g of fat for 6 months. However, results are difficult to interpret due to the unusually high fat content and the fact that data analysis was limited to only six of the obese subjects.
population in central Italy, clearly indicated that hypertriglyceridaemia is an independent risk factor for GD; this has been confirmed in various other studies [22–24], although their conclusions have been challenged [25]. The exact mechanism by which hypertriglyceridaemia increases the risk of GD is still unclear, although patients with type IV hyperlipoproteinaemia abnormalities in synthesis, pool composition and enterohepatic dynamics of bile salts [26,27], including a deficient intestinal uptake [28], have been reported. Furthermore, it must be remembered that an increase in plasma triglyceride levels is a physiological P-P event whose duration could affect lithogenic potential. In addition to obesity and metabolic factors, attention has been given to a possible impairment of GB motility in diabetic subjects, mainly due to an underlying autonomic neuropathy. Once again, studies are difficult to compare due to their heterogeneity in terms of the methods of investigation, characteristics of the GB stimuli and differences in target population. As a consequence, there are conflicting data in relation to both the increase in GB fasting volume [29–36,38–40] and P-P GB contraction [31,33–41]. Difficulties in correctly interpreting the data concerning GB kinetics are mainly due to lack of patient stratification on the basis of the presence or absence of autonomic neuropathy that has been reported to decrease GB motility [31,35–39]. Other factors possibly involved in altered GB motility include a decrease in sensitivity of GB smooth muscle to P-P levels of plasma CCK [38], and / or a reduced number of CCK receptors on the GB wall [38]. The main data concerning GB motility in diabetic patients are listed in Table 2.
2. Diabetes A two- to three-fold increase in risk of cholesterol gallstones has been reported in diabetic patients [19–21]. There are two possibly related risk factors: obesity, the role of which has been discussed above, and hypertriglyceridaemia. Data from the MICOL study [19] of a large sample of subjects representative of the general
S13
3. Coeliac disease Impaired gallbladder [42–47], stomach [48,49] and small bowel motility [50] have been reported in patients
Table 2 GB fasting volume and P-P motility according to the technique and GB stimulus used Author [Ref.]
Patients (n)
Type of GB stimulus
Technique used
GB fasting volume
P-P GB motility a
Stone [37] Shreiner [41] Fiorucci [39] Hahm [31] Chapman [32] Palasciano [35] Shaw [40] Keshavarzian [33] Wedmann [34] Mitsukawa [38]
30 8 21 24 271 21 10 47 50 28
CCK CCK Solid Solid NR Solid Liquid Solid Liquid Solid
Scintigraphy Scintigraphy US US US US US US US US
NR NR ↑ ↑ ↑ ↑ NR ND ND NR
↓ ↓ ↓ ↓ NR ↓ ↓ ND ND ↓
ND, no significant differences; NR, not reported; US, ultrasound; ↓, decreased. a Versus control.
M. Fraquelli et al. / Digestive and Liver Disease 35 ( Suppl. 3) (2003) S12 –S16
S14
Table 3 Main results of the studies evaluating fasting GB volume and P-P motility in patients with CD Author [Ref.]
Patients (n)
Type of stimulus
Technique used
GB fasting volume
P-P GB a motility
Low Beer [43] Brown [45] Fraquelli [47] Maton [51] Delamarre [46]
18 8 10 8 4
CCK analogue CCK analogue Liquid Liquid Solid
Scintigraphy Scintigraphy US US US
NR NR ↑ NR NR
↓ ↓ ↓ ↓ ↓
NR, not reported; US, ultrasound; ↓, decreased. a Versus control.
with coeliac disease (CD), and attributed to a reduced secretion of enteric hormones [44,50] or decreased sensitivity to them [45]. For the purposes of this review, we will only consider GB motility. As shown in Table 3, a number of authors have reported a reduction both in absolute and net GB emptying in response to various stimuli in untreated coeliacs, a finding that may be due to altered secretion of different GI hormones, particularly CCK. As observed by some authors [42,44,51,52] and confirmed in one of our previous studies [47], P-P CCK levels are low in untreated coeliac patients despite the concomitant increase in the number of duodenal CCK secreting cells. As a consequence of the impaired lipolysis of exogenous fat, CCK cells are not adequately stimulated to release the hormone [53], and the consequent GB inertia also contributes toward impairment of small bowel transit time and enterohepatic circulation of bile salts. Furthermore, somatostatin (SS) secretion is altered in newly diagnosed coeliac patients, as we have demonstrated in a series of patients whose fasting SS levels were significantly higher than in controls. As previously reported by Sjolund et al. [54], this may be due to an increased number of SS secreting cells, which would account for the increase in baseline GB volume. Correlation between fasting SS levels and GB size has clearly been confirmed in patients affected by somatostatinoma or treated with SS or SS analogues [55,56]. We have also found increased serum neurotensin (NT) levels in untreated coeliac patients. The physiological P-P increase in this hormone is a reliable index of nutrient delivery to ileum [57], and may impair GB motility directly or indirectly by delaying gastric emptying, as previously reported [58]. Interestingly, the GI hormone abnormalities and their effects on GB, gastric and small bowel motility normalise completely after the successful administration of a gluten-free diet [44,47,48,59]. Overall, in all the clinical conditions examined here, interesting data have emerged from the evaluation of GB motility and / or pattern of GI hormones, although it would be advisable to standardise the techniques, types of stimuli and target populations.
Conflict of interest None declared.
List of abbreviations BMI, body mass index; CCK, cholecystokinin; GB, gallbladder; GD, gallstone disease; NT, neurotensin; P-P, postprandial.
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Gallbladder motility in obesity, diabetes mellitus and coeliac disease M. Fraquelli, M. Pagliarulo, A. Colucci, S. Paggi, D. Conte* Chair of Gastroenterology, University of Milan, Milan, Italy
Abstract We reviewed data on gallbladder motility in obesity, diabetes and coeliac disease. In obesity, a condition characterised by increased risk of gallstone(s), decreased gallbladder motility has heterogeneously been reported as a consequence of the different type of meals used to induce gallbladder contraction, characteristics of the population studied, technique used, and proportion of patients with hyperinsulinaemia. Moreover, recent studies have evaluated the effect of dietary restriction on gallbladder motility in obese patients. A two- to three-fold increase in the risk of cholesterol gallstone(s) has been reported in diabetic patients, mainly in relation to obesity and hypertriglyceridaemia. Furthermore, decreased gallbladder motility has been described and attributed to other factors, including underlying autonomic neuropathy, reduced gallbladder sensitivity to cholecystokinin and / or reduced number of cholecystokinin receptors on the gallbladder wall. Impaired gallbladder motility has been reported also in patients with coeliac disease in relation to reduced secretion of enteric hormones and / or decreased gallbladder sensitivity to them. In particular, untreated coeliacs, when compared to controls, showed low postprandial cholecystokinin and increased fasting somatostatin levels. Interestingly, the correlation between fasting somatostatin levels and gallbladder size has clearly been confirmed in patients affected by somatostatinoma or treated with somatostatin or its analogues. Gallbladder motility can be affected by various clinical conditions, such as obesity, diabetes mellitus and coeliac disease. 2003 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Coeliac disease; Diabetes mellitus; Gallbladder motility; Obesity; Ultrasound
1. Obesity Obesity is a major risk factor for gallstone disease (GD) [1,2], bile super-saturation, related to the increased synthesis of cholesterol [3], being the main pathogenic factor for gallstone formation. Two other factors also play a relevant role, namely increase in fasting gallbladder (GB) volume and reduction in postprandial (P-P) GB motility. The former has been reported in a number of studies, most of which correlated with body weight, body mass index (BMI) and surface area [4,5], as well as with abdominal fat and impaired glucose tolerance, as in a metabolic syndrome characterised by central adiposity and hyperinsulinaemia [6]. Reduction in P-P GB emptying has been heterogeneously reported (Table 1), probably due to differences in the type of meal used to induce GB contraction, characteristics of the population studied (in terms of BMI, sex, etc.), and technique used to evaluate GB kinetics (i.e., scintigraphy
*Corresponding author. Tel.: 139-02-5503-3418; fax: 139-02-55033644. E-mail address: [email protected] (D. Conte).
or ultrasonography). Conflicting data may also be related to differences in the proportion of obese subjects with hyperinsulinaemia, which can decrease GB sensitivity to cholecystokinin (CCK) with a consequent reduction in GB contraction [7]. Particular interest has been shown in the effect of dietary restriction on obese patients. During rapid weight loss, a significant increase in gallstone disease (GD) has been reported repeatedly, with an overall frequency ranging from 11 to 36% [12]. The underlying pathogenic mechanisms are incompletely understood, but several factors have been considered, including an increase in cholesterol biliary output [13] and / or GB secretion of Table 1 P-P GB motility in obese subjects Author [Ref.]
Patients (n)
Meal type
Technique used
P-P GB a motility
Marzio [8] Acalovschi [9] Stone [10] Vezina [11]
21 44 7 18
Solid Solid Liquid Liquid
US US US Scintigraphy
↓ ND ND ↓
ND, no significant differences; US, ultrasound;↓, decreased. a Versus controls.
1590-8658 / 03 / $30 2003 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016 / S1590-8658(03)00087-2
M. Fraquelli et al. / Digestive and Liver Disease 35 ( Suppl. 3) (2003) S12 –S16
mucin and calcium, and a decrease in bile PGE2 and arachidonic acid levels [14,15]. A very low calorie diet also induces GB stasis, possibly as a consequence of reduced GB stimulation [12,16]. In this context, the most important factor is the actual intake of dietary fat, 10 g being the threshold amount necessary to induce efficient GB emptying [10]. This has been clearly shown by Gebhard et al. [17], who compared two different regimens of 520 kcal (with ,2 g of fat) and 900 kcal (with 10 g of fat). GD developed in 66% of patients in the first group, who also showed severely reduced GB emptying (to an average of 35%), whereas GD developed in none of the patients in the second group, who showed less reduction in GB emptying (to an average of 66%). This aspect was further investigated by Festi et al. [16], who used two isocaloric regimens of |550 kcal each, with different amount of fat (3 vs. 12.2 g / day); as expected, a significant proportion of patients on the low fat schedule developed GD (54% vs. no case in the other group) and showed a marked reduction of GB emptying (which was normal in the high fat group). In a recent study of Zapata et al. [18], incidence of GD and pattern of GB emptying were similar in 12 obese subjects and 12 healthy females given a diet of 800–1200 kcal / day with 26 g of fat for 6 months. However, results are difficult to interpret due to the unusually high fat content and the fact that data analysis was limited to only six of the obese subjects.
population in central Italy, clearly indicated that hypertriglyceridaemia is an independent risk factor for GD; this has been confirmed in various other studies [22–24], although their conclusions have been challenged [25]. The exact mechanism by which hypertriglyceridaemia increases the risk of GD is still unclear, although patients with type IV hyperlipoproteinaemia abnormalities in synthesis, pool composition and enterohepatic dynamics of bile salts [26,27], including a deficient intestinal uptake [28], have been reported. Furthermore, it must be remembered that an increase in plasma triglyceride levels is a physiological P-P event whose duration could affect lithogenic potential. In addition to obesity and metabolic factors, attention has been given to a possible impairment of GB motility in diabetic subjects, mainly due to an underlying autonomic neuropathy. Once again, studies are difficult to compare due to their heterogeneity in terms of the methods of investigation, characteristics of the GB stimuli and differences in target population. As a consequence, there are conflicting data in relation to both the increase in GB fasting volume [29–36,38–40] and P-P GB contraction [31,33–41]. Difficulties in correctly interpreting the data concerning GB kinetics are mainly due to lack of patient stratification on the basis of the presence or absence of autonomic neuropathy that has been reported to decrease GB motility [31,35–39]. Other factors possibly involved in altered GB motility include a decrease in sensitivity of GB smooth muscle to P-P levels of plasma CCK [38], and / or a reduced number of CCK receptors on the GB wall [38]. The main data concerning GB motility in diabetic patients are listed in Table 2.
2. Diabetes A two- to three-fold increase in risk of cholesterol gallstones has been reported in diabetic patients [19–21]. There are two possibly related risk factors: obesity, the role of which has been discussed above, and hypertriglyceridaemia. Data from the MICOL study [19] of a large sample of subjects representative of the general
S13
3. Coeliac disease Impaired gallbladder [42–47], stomach [48,49] and small bowel motility [50] have been reported in patients
Table 2 GB fasting volume and P-P motility according to the technique and GB stimulus used Author [Ref.]
Patients (n)
Type of GB stimulus
Technique used
GB fasting volume
P-P GB motility a
Stone [37] Shreiner [41] Fiorucci [39] Hahm [31] Chapman [32] Palasciano [35] Shaw [40] Keshavarzian [33] Wedmann [34] Mitsukawa [38]
30 8 21 24 271 21 10 47 50 28
CCK CCK Solid Solid NR Solid Liquid Solid Liquid Solid
Scintigraphy Scintigraphy US US US US US US US US
NR NR ↑ ↑ ↑ ↑ NR ND ND NR
↓ ↓ ↓ ↓ NR ↓ ↓ ND ND ↓
ND, no significant differences; NR, not reported; US, ultrasound; ↓, decreased. a Versus control.
M. Fraquelli et al. / Digestive and Liver Disease 35 ( Suppl. 3) (2003) S12 –S16
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Table 3 Main results of the studies evaluating fasting GB volume and P-P motility in patients with CD Author [Ref.]
Patients (n)
Type of stimulus
Technique used
GB fasting volume
P-P GB a motility
Low Beer [43] Brown [45] Fraquelli [47] Maton [51] Delamarre [46]
18 8 10 8 4
CCK analogue CCK analogue Liquid Liquid Solid
Scintigraphy Scintigraphy US US US
NR NR ↑ NR NR
↓ ↓ ↓ ↓ ↓
NR, not reported; US, ultrasound; ↓, decreased. a Versus control.
with coeliac disease (CD), and attributed to a reduced secretion of enteric hormones [44,50] or decreased sensitivity to them [45]. For the purposes of this review, we will only consider GB motility. As shown in Table 3, a number of authors have reported a reduction both in absolute and net GB emptying in response to various stimuli in untreated coeliacs, a finding that may be due to altered secretion of different GI hormones, particularly CCK. As observed by some authors [42,44,51,52] and confirmed in one of our previous studies [47], P-P CCK levels are low in untreated coeliac patients despite the concomitant increase in the number of duodenal CCK secreting cells. As a consequence of the impaired lipolysis of exogenous fat, CCK cells are not adequately stimulated to release the hormone [53], and the consequent GB inertia also contributes toward impairment of small bowel transit time and enterohepatic circulation of bile salts. Furthermore, somatostatin (SS) secretion is altered in newly diagnosed coeliac patients, as we have demonstrated in a series of patients whose fasting SS levels were significantly higher than in controls. As previously reported by Sjolund et al. [54], this may be due to an increased number of SS secreting cells, which would account for the increase in baseline GB volume. Correlation between fasting SS levels and GB size has clearly been confirmed in patients affected by somatostatinoma or treated with SS or SS analogues [55,56]. We have also found increased serum neurotensin (NT) levels in untreated coeliac patients. The physiological P-P increase in this hormone is a reliable index of nutrient delivery to ileum [57], and may impair GB motility directly or indirectly by delaying gastric emptying, as previously reported [58]. Interestingly, the GI hormone abnormalities and their effects on GB, gastric and small bowel motility normalise completely after the successful administration of a gluten-free diet [44,47,48,59]. Overall, in all the clinical conditions examined here, interesting data have emerged from the evaluation of GB motility and / or pattern of GI hormones, although it would be advisable to standardise the techniques, types of stimuli and target populations.
Conflict of interest None declared.
List of abbreviations BMI, body mass index; CCK, cholecystokinin; GB, gallbladder; GD, gallstone disease; NT, neurotensin; P-P, postprandial.
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