Gallbladder and gastric motility in patients with idiopathic slow-transit constipation.

Objective: Idiopathic slow-transit constipation (STC) has been suggested to be a pangastrointestinal motility disorder. We investigated scintigraphically whether motility in the gallbladder and stomach was impaired in slow-transit constipation.

Methods: Twenty-four patients with STC were studied. Colon transit time, gallbladder motility, and solid-phase gastric emptying were measured by scintigraphy.

Results: Gallbladder dysmotility was observed in 8 of 18 (44.4%) patients. Mean gallbladder ejection fraction was 41.6 [+ or -] 13.6% (range, 16.3-67.0%). Gastric emptying was delayed in 9 of 18 (50%) patients. Mean solid-phase gastric half-emptying time was 75 minutes. STC may be associated with impaired function of other gastrointestinal organs. Approximately half of patients with STC presented gallbladder or gastric dysmotility.

Conclusion: STC may not be a pure colonic abnormality; it may be a component of a pangastrointestinal tract motility disorder involving several organs.

Key Words: colon transit scintigraphy, gallbladder emptying, gastric emptying, slow-transit constipation

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Chronic idiopathic constipation caused by slow-transit constipation (STC) is one of the most common forms of constipation. STC is characterized by a lifelong history, with no identifiable etiologic factor. Bowel action may occur once every 2 to 3 weeks. Investigation reveals that these patients have a normal barium enema, delay in passage through the gastrointestinal tract, and frequently, normal rectal emptying.

The cause of STC is still uncertain, but proposed theories include a hormone disorder (1) and various degrees of intestinal neuronal agenesis. (2) However, the frequent observation in patients with STC of other disturbances involving the stomach, (3) small bowel, (4) anorectal function and the bladder, (5) blood pressure control, (6) and gastrointestinal hormone release (7) suggest that STC could be a pangastrointestinal tract motility disorder. In this study, we analyzed the emptying function of the gallbladder and stomach by scintigraphy in patients with STC, with the aim of detecting any abnormality as a component of pangastrointestinal tract motility abnormality.

Patients and Methods

More than 150 patients with chronic constipation from among 8,476 consecutive patients referred from primary care clinics were studied in Gulhane Military Medical Academy, Haydarpasa Training Hospital, Department of Gastroenterology. Subjects were studied in accordance with the ethical standards of the institution's committee on human experimentation.

All patients reported two or more criteria for constipation as defined by an international panel in Rome in 1995: (8) 1) two or fewer bowel movements per week at least 25% of the time; 2) sensation of incomplete evacuation at least 25% of the time; 3) lumpy and/or hard stools at least 25% of the time; and 4) straining at defecation at least 25% of the time. Thirty-seven patients with constipation who fulfilled the Rome criteria, and who had undergone more than 2 years of unsuccessful treatment of dietary fiber supplements and oral laxatives, entered the study. The exclusion criteria consisted of the following: 1) organic colonic disease shown by colonoscopy and/or barium enema; 2) previous abdominal surgery; 3) diabetes or other systemic metabolic disease; and 4) gallstones confirmed by ultrasound.

Colon transit scintigraphy was performed in all patients with chronic idiopathic constipation. Patients with STC were evaluated for gallbladder and gastric emptying by scintigraphy.

Colon Transit Scintigraphy

All patients underwent colon transit scintigraphy. During the test week, oral laxatives or cleansing enemas were withdrawn. No effort was made to control patients' diets during the scan period.

Subjects attended the nuclear medicine department on a Monday morning and were given 10 to 11 MBq gallium citrate Ga 67 orally at approximately 9 AM. They returned the same day at approximately 2 PM, and on subsequent days at approximately 24, 48, 72, 96, 120, and 144 hours after oral administration. On each occasion, anterior and posterior abdominal views were obtained for 10 minutes using a large field of view gamma camera (ADAC Genesys; ADAC Laboratories, Milpitas, CA) and a medium-energy collimator (peaked for 93, 185, and 300 KeV). To correct for tissue attenuation, each view was immediately followed by a posterior view. Radioisotope counts were quantitatively determined. Regional colonic radioisotope movement was assessed from regions of interest created by visually analyzing the full sequence of scans (caecum and ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon, and rectum). Activity-time curves for each region of interest allowed for evaluation of the proportion of radioisotope spent in each region over the scanning period, indicating the site of segmental colonic delay. Delayed total colonic transit was defined as a total colon transit time (CTT) longer than 72 hours. (9)

Gallbladder Emptying

Subjects were studied after an overnight fast and arrived at the nuclear medicine department at 11 AM. All patients with STC were given 5 [mu]Ci technetium Tc 99m-labeled trimethyl-3-bromo iminodiacetic acid as an intravenous bolus. With patients in the supine position, anterior images of the gallbladder were acquired in 60-second time frames in a 64 X 64 matrix using a gamma camera (ADAC Genesys) with a low-energy parallel collimator (peaked for 140 KeV [+ or -] 20% window) linked to a Pegasys-Sun computer system (ADAC Laboratories). Regions of interest were drawn around the gallbladder, and activity-time curves were generated after correction for background.

Once gallbladder activity peaked, each patient drank a liquid test meal--30% lipid, 16.7% protein, and 53% carbohydrate (Ensure Plus; Abbott Laboratories, Abbott Park, IL [375 kcal/250 ml])--at room temperature over 1 minute. After completion of the test meal, data acquisition was continued for an additional 30 minutes. Time of onset and completion of gallbladder contraction were identified by activity-time curves for each individual. Gallbladder ejection fraction (GBEF) was calculated as net peak fasting activity--net through postprandial activity/net peak fasting activity X 100. The lower limit of normal GBEF was accepted as 40%. (10) GBEF less than 40% was defined as biliary dyskinesia.

Gastric Emptying

Subjects were studied after an overnight fast and arrived at the nuclear medicine department at 9 AM. A standard test meal of 400 to 500 [mu]Ci of technetium Tc 99m-sulfur colloid incorporated into egg white was ingested. With patients in the standing position, anterior and posterior images of the stomach were acquired every 15 minutes for 120 minutes. Regions of interest were drawn around the stomach. A gamma camera (ADAC Genesys) with a low-energy parallel collimator (peaked for 140 KeV [+ or -] 20% window and 256 matrix static image) linked to a Pegasys-Sun computer system was used. Gastric emptying was expressed as T1/2, the time taken for counts to fall to one-half of the peak value. The upper limit of normal was accepted as 60 minutes for solid-phase gastric emptying. (11)

Statistical Analysis

Data were analyzed using the statistical software package SPSS 7.5 for Windows (SPSS, Inc., Chicago, IL). Results were expressed as mean (and SD or SEM) or median (minimum-maximum). One group Kolmogorov-Smirnov test was used for normal distribution. Statistical comparisons for means of two independent groups were conducted using the t test, the [chi square] test, and Fisher's exact [chi square] test. Correlation results were calculated with the Pearson test. The level of significance was set at P < 0.05.

Results

Of the 24 patients with STC, 18 were women and 6 were men. Mean age was 49.2 [+ or -] 18.6 years. Mean duration of constipation was 7.5 years (range, 2-50 years). The incidence of spontaneous defecations ranged between one every 4 days to one every 14 days, with a mean of one every 6 days.

All 24 patients underwent evaluation with colon transit scintigraphy. CTT in patients with STC (CTT > 72 hours) was 73 to 96 hours in 6 (25%), 97 to 120 hours in 16 (66.6%), and greater than 144 hours in 2 (8.3%) patients (Fig. 1). Segmental slowing was observed at the right colon in 1 (4.1%), left colon in 3 (12.5%), pancolonic in 3 (12.5%), rectosigmoid in 4 (16.7%), and left colon with rectosigmoid in 13 (54.2%) of the 24 patients with STC (Fig. 2).

Gallbladder and gastric motility were studied in 18 of 24 patients with STC (6 patients were excluded because of diverticular disease, diabetes, hypothyroidism, gallstones, and 2 patients were excluded because of lack of consent). Gallbladder dysmotility (GBEF < 40%) was observed in 8 of 18 (44.4%) patients. Mean gallbladder ejection fraction was 41.6 [+ or -] 13.6% (range, 16.3-67.0%). The GBEF of patients with STC according to the CTT is shown in Figure 3. Delay of CTT (P = 0.589, r = 0.137) and slowing of segmental gut transit (P = 0.387, r = 0.417) were not correlated with reduced GBEF.

[FIGURE 1 OMITTED]

Nine of 18 patients (50%) with STC had delayed solid-phase gastric emptying (>60 minutes). Mean solid-phase gastric half-emptying time was 75 minutes (Fig. 4). Solid-phase gastric emptying of the patients with STC according to the CTT is shown in Figure 5. Delayed CTT (P = 0.709, r = 0.094) and slowing of segmental gut transit (P = 0.629, r = 0.653) were not correlated with delayed gastric emptying. In 5 of 18 patients (27.7%) with STC, both gallbladder dysmotility and gastric dysmotility were observed.

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Discussion

Symptoms of constipation may result from a variety of diseases, and patients with constipation can be regarded as a heterogeneous group. STC has some characteristic features, such as predominance in young female patients, frequent onset during childhood, unresponsiveness to bulk laxatives and stool softeners, infrequent spontaneous defecations associated with abdominal discomfort, apparent normality of the colon, and frequent association with other minor complaints related to hollow-organ dysfunction. Association of STC with gastrointestinal or urinary tract dysfunction or orthostatic hypotension, and suggestions of a possible involvement of the autonomic nervous system have been reported by other authors. (3) (12-14) There is increasing evidence that idiopathic STC is a distinct clinical entity comprising a pangastrointestinal tract motility disorder. (6) (15) In our study, the motility of the gallbladder and stomach in patients with STC was evaluated with the use of scintigraphy. Although some authors have shown that small-bowel transit was also delayed in patients with STC (2), (4), we were unable to study this. Our results point to the existence of motility defects of the gallbladder or stomach, although the presenting complaint was severe constipation.

[FIGURE 4 OMITTED]

The present study shows that STC is associated with significant impairment of the motility of the gallbladder and stomach. In our study, abnormal gallbladder and stomach motility was frequent, occurring in 44% (8 of 18) and 50% (9 of 18) of patients, respectively.

[FIGURE 5 OMITTED]

One aspect of our study that requires further explanation is the normal value for gallbladder emptying. A lower limit of 40% for normal gallbladder emptying was calculated using the mean [+ or -] 3 SEM in a study of 74 volunteers by Yap et al. (10) On the basis of this criterion, 8 of 18 (44.4%) patients with STC in the present study had an abnormally low GBEF. Mean GBEF was 41.6 [+ or -] 13.6% (range, 16.3-67.0%). We also found that delay of both total and segmental CTT was not correlated with decreased GBEF.

Hemingway et al (11) screened patients with idiopathic STC to determine gallbladder function by cholecystokinin (CCK)-augmented trimethy1-3-bromo iminodiacetic acid scans. Eight of 10 patients in that study had low GBEF, and median GBEF was 28.5%.

Employing ultrasound and the CCK-analogue cerulein, Neri et al (16) assessed the gallbladder motor response to physiologic and hormonal stimuli in six patients. They showed a greater gallbladder contraction in response to the meal and to cerulein.

In the study by Altomare et al, (17) it has been demonstrated that in the majority of patients with STC, motility disorders of the gastrointestinal tract and sometimes the gallbladder often coexist. Gallbladder motility was studied with the use of ultrasound and liquid test meal. Gallbladder dysmotility was observed in 6 of 14 patients (43%).

Penning et al, (18) used ultrasound to study gallbladder emptying in response to neural, cephalic-vagal (modified sham feeding), and hormonal (CCK) stimulation. Their results showed that patients with STC have smaller fasting gallbladder volumes, impaired gallbladder responses to vagal cholinergic stimulation, but normal gallbladder responses to hormonal stimulation with CCK. Fasting plasma CCK concentrations of patients with STC were not different from those in control subjects. Also, reduced plasma peptide YY (which induces relaxation of the gallbladder) concentrations may account for the reduction in fasting gallbladder volume. (19), (20) There was no correlation between individual body-mass index and fasting gallbladder volume. The small fasting gallbladder volume was not likely attributable to increased vagal tone because recent studies indicate that STC may be associated with autonomic neuropathy. (12) Reduced gallbladder contraction in response to modified sham feeding pointed to impaired vagal cholinergic transmission, which is in line with the findings of parasympathetic autonomic neuropathy in the study by Altomare et al. (17) Abnormalities of the colonic myenteric plexus in STC might be another explanation for the impaired response of the gallbladder to modified sham feeding. (15)

Delayed CTT and gallbladder dysfunction may be linked to two findings. The increase in hepatic bile entering the proximal intestine could lead to greater exposure of bile salts to the anaerobic bacteria responsible for biotransformation of hydrophilic bile salts to more hydrophobic bile salts. (21) An increase in these salts in the enterohepatic circulation might further impair gallbladder motility, as they have been shown to have a direct effect on the gallbladder. The biliary proportion of hydrophobic deoxycholic acid also been suggested to be greater in patients with constipation than in healthy subjects. (21)

Defective gallbladder emptying observed in patients with STC may also be secondary to altered postprandial gastric emptying, because in our study, 27.7% (5 of 18) of patients with STC also had impaired gastric emptying. (17) This may be caused by a cologastric reflex produced by colonic distension rather than by an impairment of autonomic nerves.

Our findings of gastric dysmotility in 44.4% (8 of 18) of patients with STC confirm previous results by Hemingway et al (11) and Altomare et al, (15) who found delayed gastric emptying in 100% (n=10) and 76% (n=17) of patients, respectively. The discrepancy in results between our study and those of Neri et al, (16) Hemingway et al, (11) Altomare et al, (17) and Penning et al (18) may be related to patient selection, measurement techniques (scan versus ultrasound), or infusion of CCK.

In this study, with the use of scintigraphy for the gallbladder and stomach, we have demonstrated that in the majority of patients with STC, motility disorders of the gallbladder or stomach often coexist. Demonstrating the presence of abnormal gallbladder or stomach function in patients with STC supports the view that STC is a distinct clinical entity within the spectrum of patients who present with severe constipation. Inclusion of the investigation of gallbladder and stomach function in the workup of patients with severe constipation may be beneficial and allow selection of this specific subgroup.

Conclusion

Gallbladder motility or gastric emptying is affected in patients with STC. In addition to the colon, the function of proximal gastrointestinal organs such as the gallbladder and stomach is also affected in STC. STC may not be a pure colonic disease; it may be a component of a generalized disorder of gastrointestinal tract motility that involves several gastrointestinal organs.

Key Points

* Idiopathic slow-transit constipation (STC) has been suggested to be a pangastrointestinal motility disorder rather than a pure colonic pathology.

This study used scintigraphy to investigate whether motility in the gallbladder and stomach, considered separately from the colon, were impaired in patients with STC.

Gallbaladder dysmotility was observed in 44.4% of patients, and delayed gastric emptying was observed in 50% of patients.

Results of the current study suggest that STC should be considered a distinct clinical entity within the spectrum of patients who are presenting with severe constipation. Investigation of gallbladder and stomach function in the workup of patients with severe constipation may be beneficial and allow selection of this specific subgroup.

Fig. 1 Graph showing colon transit times of patients with slow-transit
constipation

Colon transit time (hours)  Number of patients

         73-96                      6
         97-120                    16
        121-144                     0
           >144                     2

Note: Table made for bar graph.

Fig. 2 Graph showing segmental showing of colon transit in patients with
slow-transit constipation. RS, rectosigmoid; Pan, pancolonic

Segmental slowing of colon transit  Number of patients

              Right                     1  (4.1%)
              Left                      3 (12.5%)
              RS                        4 (16.7%)
              Left+ RS                 13 (54.2%)
              Pan                       3 (12.5%)

Note: Table made for bar graph.

Accepted August 29, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9702-0124

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Alp Gunay, MD, A. Kemal Gurbuz, MD, Yavuz Narin, MD, A. Melih Ozel, MD, and Y. Yazgan, MD

From the Departments of Gastroenterology and Nuclear Medicine, Gulhane Military Medical Academy, Haydarpasa Training Hospital, Istanbul, Turkey.

No financial support or provision of supplies was received for use in our study. We do not have any commercial, financial or proprietary interest in any drug, device, or equipment mentioned in the submitted original article. Institutional review board approval was received.

Reprint requests to Alp Gunay, MD, Gastroenteroloji Uzmani, Golcuk Deniz Hastanesi Gastroenteroloji Klinigi, Golcuk/Kocaeli, Turkey. Email: [e-mail]