Surgical Endoscopy And Other Interventional Techniques

, Volume 20, Issue 9, pp 1364–1367

Proton pump inhibitors reduce gallbladder function

Authors

  • M. A. Cahan
    • Department of SurgeryUniversity of North Carolina at Chapel Hill
  • L. Balduf
    • Department of SurgeryUniversity of North Carolina at Chapel Hill
  • K. Colton
    • Department of SurgeryUniversity of North Carolina at Chapel Hill
  • B. Palacioz
    • Department of SurgeryUniversity of North Carolina at Chapel Hill
  • W. McCartney
    • Department of RadiologyUniversity of North Carolina at Chapel Hill
    • Department of SurgeryUniversity of North Carolina at Chapel Hill
Article

DOI: 10.1007/s00464-005-0247-x

Cite this article as:
Cahan, M.A., Balduf, L., Colton, K. et al. Surg Endosc (2006) 20: 1364. doi:10.1007/s00464-005-0247-x

Abstract

Background

In the authors’ previous study of gallbladder function before and after fundoplication, 58% of the patients demonstrated preoperative gallbladder motor dysfunction, and 86% of those retested after operation and cessation of proton pump inhibitors (PPIs) normalized. Because no study has directly assessed the impact of antisecretory agents on gallbladder function, this study measured gallbladder ejection fraction (GBEF) in healthy volunteers before and after initiation of PPIs.

Methods

A total of 19 subjects completed the study, which included baseline determination of GBEF by cholecystokinin-stimulated hepatobiliary acid scan, 30 days of antisecretory therapy with omeprazole (40 mg daily), and repeat GBEF on day 30. Subjects were surveyed regarding compliance and symptoms.

Results

For 15 of 19 subjects, PPI therapy was associated with reduced gallbladder motility. Evolution of symptoms consistent with a biliary etiology was reported by 26.7% of these subjects.

Conclusions

Short-term PPI therapy reduces gallbladder motility in healthy volunteers. Chronic PPI therapy may pose a risk for long-term gallbladder dysfunction and biliary complications.

Keywords

Biliary dyskinesiaGallbladder ejection fractionGastrinGERDProton pump inhibitors

A prior study intended to determine the value of preserving hepatic branch vagal fibers during Nissen fundoplication measured cholecystokinin (CCK)-stimulated gallbladder ejection fraction (GBEF) before and after surgery [17]. Unexpectedly, this study found that 58% of patients with preoperative gastroesophageal reflux (GER) had abnormally low gallbladder function. More surprisingly, 86% of these patients had normalized gallbladder function after fundoplication. We hypothesized that proton pump inhibitor (PPI) therapy may have been associated with gallbladder motor dysfunction in the preoperative patients, and that cessation of PPIs accounted for the normalization in GBEF after antireflux surgery.

The existence of an association between gallbladder disorders and GER remains controversial. Investigators have previously shown that patients with gallstones are more likely to have hiatal hernias [5], impaired gastric motility, and abnormal gastroesophageal pH profiles [19]. However, more recent reports have failed to demonstrate an association between cholelithiasis and GER [1, 16]. No study has investigated whether acid suppression with medications has an impact on gallbladder function.

Gastroesophageal reflux is common throughout the United States [11], and PPIs currently are the treatment of choice for most Americans with a diagnosis of chronic GER. In 2002, PPIs represented the eighth most commonly prescribed class of drugs [25]. However, despite the common use of PPIs for patients with GER and the debate over an association between GER and gallbladder disease, no study has specifically examined whether treatment by antisecretory medications has an impact on gallbladder motor function. Therefore, to determine whether gallbladder function is reduced by chronic PPI therapy, we measured changes in the GBEF of normal volunteers before and 1 month after a course of PPI therapy was initiated.

Materials and methods

Healthy volunteers were recruited by advertisements in newspapers and on campus. Using standardized questionnaires, respondents were screened for exclusion criteria, which specified a history of peptic ulcer disease, cholecystectomy, chronic abdominal pain, or gastroesophageal reflux. Individuals meeting the entry criteria were seen in the clinic and consented to participate in the study. Female volunteers of childbearing age who agreed to participate in the study were screened by a urine pregnancy test. The subjects who completed all phases of the study were compensated for their time.

All the subjects who consented to this institutional review board–approved study submitted to baseline determination of GBEF by CCK hepatobiliary acid (HIDA) scan, treatment with omeprazole 40 mg daily for 4 weeks, and repeat CCK-HIDA immediately after cessation of medication. Initially, 22 patients agreed to participate, but 2 patients withdrew before the second CCK-HIDA scan. Another patient had nonfilling of the gallbladder for 2 h at the second HIDA scan, and because no GBEF was calculated, she was excluded. A total of 19 patients (mean age, 40.8 years, 78.9% female) completed both CCK-HIDA scans and were included in the paired-samples analysis.

The CCK-HIDA scans involved intravenous injection of technetium (5 mCu) and scintigraphic measurement of its biliary excretion over a period of 1 to 2 h. Gallbladder ejection fraction was defined as the change in gallbladder activity after intravenous administration of CCK (0.04 μg/kg administered over 19 min). At completion of the study, the participants completed a questionnaire regarding medication compliance and evolution of possible biliary symptoms including abdominal pain, nausea, vomiting, or increased flatulence. On-therapy GBEF was compared with pre-therapy GBEF using a paired t-test.

Results

In 15 of the 19 subjects, 1 month of PPI therapy was associated with reduced gallbladder motility (Fig. 1). Five of these patients (26.3%) had a GBEF less than 35% before PPIs, whereas 10 patients (52.6%) had a GBEF less than 35% while receiving PPIs (Table 1). The mean GBEF decreased from 56.4% ± 30.0% to 42.8% ± 32.3% (p < 0.01, paired t-test). Some form of discomfort during one of the HIDA scans was reported by 6 (40%) of 15 individuals.
https://static-content.springer.com/image/art%3A10.1007%2Fs00464-005-0247-x/MediaObjects/464_2005_247_f1.jpg
Fig. 1

Percentage change in gallbladder ejection fraction for individual patients after 1 month of proton pump inhibitor (PPI) therapy.

Table 1

Gallbladder function in patients with gastroesophageal reflux (GER) before and after proton pump inhibitor (PPI) therapy

Patient

Compliant

Pre-PPI GBEFa

Symptoms at HIDA-1?

Symptoms during interval?

Post-PPI GBEFa

Symptoms at HIDA-2?

1

Yes

42

No

No

31

No

2

ND

91

ND

ND

93.3

ND

3

No

62

No

Yes

32

Yes

4

Yes

74.7

Yes

Yes

48.9

No

5

Yes

41

Yes

No

29.8

No

6

No

11

Yes

No

3

Yes

7

ND

45.5

ND

ND

72.8

ND

8

ND

13

ND

ND

10.8

ND

9

Yes

25

No

No

6

No

10

Yes

23.7

Yes

No

6.3

Yes

11

Yes

67.4

No

No

70.3

No

12

Yes

47.9

Yes

No

43

Yes

13

Yes

92.6

No

No

85.7

No

14

Yes

60.3

No

No

25.1

No

15

Yes

12.9

No

Yes

3.4

No

16

Yes

89.3

No

No

12.9

No

17

Yes

88

No

No

88

No

18

ND

94

ND

ND

71.7

ND

19

Yes

90.2

No

Yes

80

No

GBEF, gallbladder ejection fraction; HIDA, hepatobiliary acid; ND, no data

a Bold indicates CCK-stimulated GBEF less than 35%

A total of 15 individuals responded to the study compliance and symptom inventory. Of these 15 individuals, 13 (86.7%) reported full compliance with the study medication, whereas 2 of the 15 reported missing fewer than three doses. New symptoms of abdominal pain, nausea, vomiting, or increased flatulence while taking PPIs were reported by 4 (26.7%) of 15 subjects, and all of these were among the subjects with diminished GBEF after 30 days of PPI therapy (Table 1).

Discussion

We found 15 of our 19 subjects had decrease in CCK-stimulated GBEF after 1 month of PPIs, and 4 of these individuals reported new symptoms consistent with a biliary etiology on a poststudy questionnaire. On the basis of these findings and those of our prior study, namely, improved GBEF after antireflux operation and PPI cessation, we conclude that PPI therapy is associated with gallbladder motor dysfunction.

Although chronic acid suppression with PPIs results in duodenal alkalinization [2, 18], which is associated with a reduction in CCK release [21], these normal physiologic effects of PPI therapy do not explain our finding of decreased GBEF on administration of exogenous CCK. We propose that chronic PPI therapy diminishes the gallbladder’s intrinsic ability to respond to CCK and suggest several explanations.

Chronic PPI use may affect receptor competition or downregulation. Contractility of the gallbladder is directly related to CCK-A receptors located in the smooth muscle layer of the organ [23]. Because suppressed levels of endogenous CCK would be unlikely to induce downregulation of receptors, we suggest that PPI-induced hypergastrinemia may be responsible for either CCK-A receptor competition or downregulation. Findings have shown that PPI therapy results in dose-dependent increases in serum gastrin [4, 20], which occur early after initiation of PPIs, are maintained during chronic therapy, and recover quickly after cessation [10, 13]. There is a chemical similarity in the biologically active C-terminal regions of gastrin and CCK [26], as well as an overlap in functionality of these peptides in experimental models [7, 12, 22, 26]. Gastrin has been shown to reduce the ability of CCK to increase intraluminal pressure in the opossum gallbladder, and competition between gastrin and CCK for a common receptor on cat gallbladder also has been documented [8]. Likewise, synthetic human gastrin has an independent stimulatory effect on gallbladder motility in humans [26], thereby supporting the possibility that increases in endogenous gastrin could have an effect at the CCK-A receptor in humans. Finally, clinical data showing that 71% of Zollinger-Ellison syndrome patients with persistent hypergastrinemia have evolution of gallstones after palliative gastrectomy [6] provide strong circumstantial evidence suggesting a role for gastrin in this association.

Another possible etiology of diminished GBEF is outflow resistance. Disruption of autonomic or hormonal stimuli for sphincter of Oddi relaxation may have an adverse impact on GBEF. Because CCK normally inhibits the phasic activity of the sphincter of Oddi to increase the flow of bile [24], suppressed levels of endogenous CCK from chronic PPI therapy would be expected to increase sphincter of Oddi tone and cause relative outflow obstruction. A similar pathophysiology has been postulated for the purported causes of biliary dyskinesia: sphincter of Oddi spasm (SOS) and cystic duct syndrome (CDS) [15]. Both SOS and CDS are characterized by a paradoxical effect of CCK on the sphincter and the cystic duct. Finally, patients with chronic cholecystitis also have been shown to have decreased GBEF on CCK-HIDA, presumably from cystic duct spasm [14]. Therefore, the effect seen in our subject group may be explained by alterations in biliary physiology that generate increased resistance in the extrahepatic biliary tract, and thereby reduced GBEF.

Reductions in gallbladder emptying also may be a consequence of PPI-induced variations in gastroduodenal motility. Healthy men treated for 10 days with PPIs have decreased rates of gastric emptying, along with elevated serum gastrin and decreased CCK levels [21]. An association between gastric emptying delay and gallbladder motor dysfunction has been shown in patients with diabetes [3] and those with cholelithiasis [19]. Reduction in gastric emptying during PPI therapy may reduce GBEF by mechanisms other than those already proposed.

In considering the limitations of this study, we note that the HIDA scan, although a powerful diagnostic tool, has limitations including false-positives in cases of total parenteral nutrition, liver disease, insufficient fasting, hyperbilirubinemia, and opiate or alcohol abuse [9]. In addition, the symptom survey used was not a validated tool, and because it was administered after the study, may have resulted in bias among participants. Finally, because of the small sample size and the limited duration of the study, we cannot clearly associate changes in GBEF with evolution of symptoms, or explain why there is a single outlier whose GBEF increased.

Conclusion

Although the mechanism and clinical significance of the association between PPIs and biliary motor dysfunction are not yet defined, we suggest that patients with GER who experience nausea, vomiting, or abdominal pain during chronic PPI therapy should be considered for anatomic and/or functional evaluation of the gallbladder before PPI dosage escalation or referral for antireflux surgery. In addition, providers should seek objective evidence of GER before recommending chronic PPI therapy, and should be aware of evolving data regarding the impact of such therapy on biliary function.

Copyright information

© Springer Science+Business Media, Inc. 2006