Dig Dis Sci (2014) 59:2850–2863 DOI 10.1007/s10620-014-3342-9

REVIEW

Cholecystectomy for Biliary Dyskinesia: How Did We Get There? Klaus Bielefeldt • Shreyas Saligram • Susan L. Zickmund • Anwar Dudekula Mojtaba Olyaee • Dhiraj Yadav

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Received: 13 February 2014 / Accepted: 19 August 2014 / Published online: 6 September 2014 Ó Springer Science+Business Media New York 2014

Abstract Background The focus of biliary dyskinesia (BD) shifted within the last 30 years, moving from symptoms after cholecystectomy (CCY) to symptoms with morphological normal gallbladder, but low gallbladder ejection fraction. Methods We searched the pubmed database to systematically review studies focusing on the diagnosis and treatment of gallbladder dysfunction. Results Impaired gallbladder contraction can be found in about 20 % of healthy controls and an even higher number of patients with various other disorders. Surgery for BD increased after introduction of laparoscopic CCY, with BD now accounting for[20 % of CCY in adults and up to 60 % in pediatric patients. The majority of cases reported were operated in the USA, which differs from surgical series for cholelithiasis. Postoperative outcomes do not differ between groups with abnormal or normal gallbladder function. Conclusion Functional gallbladder testing should not be seen as an indicator of relevant biliary tract disease or prognostic marker to identify patients who may benefit

K. Bielefeldt (&)
D. Yadav Divisions of Gastroenterology, University of Pittsburgh Medical Center, 200 Lothrop St., Pittsburgh, PA 15213, USA e-mail: [email protected] S. Saligram
S. L. Zickmund
A. Dudekula General Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA S. Saligram
M. Olyaee Divisions of Gastroenterology, Kansas University of Medical Sciences, Lawrence, KS, USA S. L. Zickmund Center of Health Equity Research and Practice, Veteran Administration Health System Pittsburgh, Pittsburgh, PA, USA

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from operative intervention. Instead biliary dyskinesia should be considered as a part of a spectrum of functional disorders, which are generally managed conservatively. Small proof of concept studies have demonstrated effects of medical therapy on biliary dysfunction and should thus be never tested in appropriately designed trials. Keywords Biliary diseases
Gallbladder ejection fraction
Cholecystectomy
Biliary dyskinesia
Abdominal pain
Functional gastrointestinal disorders

Introduction Close to 130 years after Carl Langenbuch’s first successful operation [1], cholecystectomies are among the most common abdominal surgeries. For many decades, physicians relied on symptoms and clinical findings. However, dyspeptic symptoms and right-sided abdominal tenderness are nonspecific and can be found in many patients without biliary tree disease. It may thus not be surprising that soon after its introduction, the first account of a cholecystectomy without stone disease was published [2]. Such findings were noticed more often and were associated with poor postoperative outcomes [3]. Even in patients with gallstone disease, symptoms persisted in around 20 % after gallbladder removal [4, 5]. While some of these cases were explained by choledocholithiasis, a substantial number of patients did not have identifiable abnormalities in the biliary tree. A German physiologist provided a potential explanation for this scenario by studying the guinea pig biliary tree [6]. He described biliary dyskinesia during high-intensity stimulation of vagal efferents. It caused gallbladder contraction and contraction of the sphincter of Oddi (‘‘hyperkinetic dyskinesia’’), and during splanchnic stimulation,

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there was contraction of the sphincter of Oddi (‘‘akinetic dyskinesia’’) but relaxation of gall bladder. Clinicians accepted biliary dyskinesia of the ductal system as a cause for persisting symptoms after cholecystectomy and performed surgeries targeting the splanchnic innervations, vagal innervations, or cutting the sphincter of Oddi [4, 7, 8]. Within the last 40 years, imaging studies were developed that assess gallbladder function in humans and that led to the identification of patients with abdominal complaints and impaired gallbladder contraction [9–11]. Thus, clinicians started applying the term biliary dyskinesia to the changes in gallbladder rather than ductal or sphincter function. Less than 25 years ago, a surgical report dismissed the dyskinesia as a radiological finding rather than an indication for surgery [12]. Prior reviews shared concerns about the specificity of functional testing for biliary dyskinesia [4, 13–16]. Even though only a single small randomized controlled trial has been performed [17], cholecystectomy has become ‘‘standard therapy’’ for biliary dyskinesia [18–20]. While experts consider biliary dyskinesia a ‘‘rare disorder’’ [21], this diagnosis is among the most common indication for cholecystectomy in children and accounts for up to 20 % of all gallbladder removals in adults [22–27]. Considering this discrepancy between expert opinion and clinical reality, it is time to review the evolution of biliary dyskinesia as a disorder of the gallbladder, analyze time and regional trends, and address the validity of currently used diagnostic and therapeutic strategies. Our goal was to provide a framework for alternative approaches in this increasingly common problem.

The Evolution of Biliary Dyskinesia as a Disorder of the Gallbladder Prior to 1970, few investigators speculated on the cause of presumably typical biliary symptoms in the absence of gallstones during surgery. Hogan and Geenen [31] as well as Grace et al. [32] defined biliary dyskinesia as a ‘‘primary disorder of the tonic or phasic motor activity of the sphincter of Oddi’’ [32]. However, by combining cholecystography and later ultrasound examinations with stimulating meals, cholecystokinin (CCK) or its synthetic analog, radiographic, or sonographic assessment of gallbladder function became possible in humans [9, 10]. The introduction of scintigraphic methods allowed close temporal monitoring of bile excretion, accumulation, and ejection from the gallbladder [28]. With the development and adoption of laparoscopic cholecystectomy [29, 30], the number of elective biliary surgeries increased significantly, as did case series reporting operative interventions for biliary dyskinesia (Fig. 1).

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Fig. 1 Evolution of biliary dyskinesia as a disorder of the gallbladder. a Depict the number of publications indexed in the PubMed data base that focus on biliary dyskinesia as a gallbladder disorder. b The number of patients undergoing cholecystectomy for biliary dyskinesia each year based on published case series. Data for adult patients are indicated by black circles, pediatric patients by white circles

With a delay of about 7 years, articles about biliary dyskinesia in children began to appear in the surgical literature (Fig. 1). In adults, biliary dyskinesia accounted for 4–15 % of the total volume of gallbladder surgery before 2000 [26, 33–37]. During the same time frame, only a single pediatric report cited two cases of biliary dyskinesia among a total of 100 cholecystectomies [24]. Within the last 10 years, the scenario has changed with only one large case series from 2000 showing a low fraction of patients operated for biliary dyskinesia [38], while three other publications quoted rates between 26 and 38 % for adults [39–41] and between 13 and 63 % for children [22, 42–46]. Beyond the temporal evolution of biliary dyskinesia as an indication for surgery, published case series for biliary dyskinesia show an interesting geographic distribution with about 80 % of the operations performed in the USA (Table 1) [9, 11, 14, 17, 22, 25, 34, 37–40, 47–78]. This fact contrasts with reports on operations for symptomatic gallstone disease; a review of 50 consecutive full-length articles revealed that less than 20 % of the publications originated in the USA (Table 1) [5, 79–126].

Expert Definition of Biliary Dyskinesia Medical and surgical review articles all agree on the importance of episodic pain, located in the epigastrium or right upper quadrant and triggered by food intake, combined with documented impairment of gallbladder function as defined by a decreased ejection fraction. This is as per

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Table 1 Geographic distribution of published case series reported surgeries for biliary dyskinesia or cholelithiasis (for details and citation, please see text) Area of origin

Table 2 Rome III criteria for functional gallbladder disorder (for details and citation, please see text) Functional gallbladder disorders: Diagnostic criteria must include episodes of pain located in the epigastrium and/or right upper quadrant and all of the following

Biliary dyskinesia

Cholelithiasis

Case series

Patients

Case series

47

2,625

6

359

The pain builds up to a steady level

2

89

1

397

1

22

The pain is moderate to severe enough to interrupt the patient’s daily activities or lead to an emergency department visit The pain is not relieved by bowel movements

Patients

Episodes lasting thirty minutes or longer Recurrent symptoms occurring at different intervals (not daily)

USA Canada Mexico South America

1

84

Europe

5

259

18

5,982

Asia

3

117

17

17,301

Australia and New Zealand

3

77

Africa and Arab Peninsula

The pain is not relieved by postural change The pain is not relieved by antacids Exclusion of other structural disease that would explain the symptoms

6

2,238

Supportive criteria: the pain may present with one or more of the following Associated with nausea and vomiting

Rome III consensus, which is summarized in Table 2 [21]. Views differ slightly when it comes to treatment. Most surgical authors emphasized the good results after cholecystectomy, describing cure or improvement rates of 80–100 % [18, 20, 127, 128]. This contrasts with a slightly more cautious interpretation by others, who still supported cholecystectomy as treatment of choice, but emphasized the need for further studies [13, 19, 27, 28, 129–133]. Interestingly, experts convened during the Rome III consensus conference used the response to surgery, assessed 12 months after the intervention, as indirect confirmatory evidence that the biliary tree was indeed the cause of symptoms [21]. While not explicitly stated, the required time frame of 12 months decreases but does not eliminate the chance of a mere placebo effect, which should decline over time. While a single randomized controlled trial demonstrated persistent symptoms in the small group of patients treated expectantly [17], these results contrast with studies that show significant fluidity of functional gastrointestinal syndromes and even symptomatic gallstone disease [134– 136]. More importantly, this approach relies on outcome after organ removal to define the presence of illness in the very same organ, an obviously unusual criteria that suggest a surgical treatment before definitively making the diagnosis. As the expert consensus defined biliary dyskinesia by symptoms and a decreased ejection fraction [21], it is unclear whether functional biliary testing is reliable.

Defining Normal Gallbladder Function in Humans The introduction and use of diagnostic testing rely on reference values of normal results typically obtained in healthy volunteers. Two different methodologies, ultrasound and

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Radiates to the back and/or right infra subscapular region Awakens from sleep in the middle of the night Functional gallbladder disorder: diagnostic criteria must include all of the following Criteria for functional gallbladder Gallbladder is present Normal liver enzymes, conjugated bilirubin, and amylase/lipase

HIDA scanning, have been assessed more extensively providing a range of normal values. Independent of the methodology, data were reasonably reproducible in healthy controls, whether studies were performed using a test meal, chemical stimulus, or scintigraphy [137–141]. Using ultrasound-based assessment of gallbladder volume before and after a test meal, studies reported mean ejection fractions between 37 and 81 % (Fig. 2a) [138, 142, 146–172]. Two studies examined the effect of CCK infusion on gallbladder emptying and did not demonstrate a significant difference compared to meal stimulation [142, 173]. These results are similar to those obtained with cholescintigraphy and meal stimulation (Fig. 2b) [138, 139, 142, 174–185] or CCK or its synthetic analog sincalide (Fig. 2c) [137, 140–145, 165, 186–198]. Ultrasound imaging typically showed a gradual volume increase 30–60 min after meal or agonist stimulation, while the scintigraphic method demonstrated continuing decrease, likely due to the progressive washout of the tracer [138, 142]. In order to minimize variability due to gastric emptying, most investigators and clinicians prefer cholecystokinin (CCK) or its analog sincalide, given as a slow agonist infusion to minimize symptoms and variability [15]. While now routinely used to diagnosis of biliary dyskinesia, abnormal results can be seen in healthy volunteers. One of the methodological studies excluded 8 of 21 healthy volunteers because of an abnormal gallbladder ejection

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Fig. 2 Bar graph showing published data on gallbladder emptying in asymptomatic controls, examined with ultrasound (a) or HIDA scan (b) after a fatty meal or using CCK/sincalide stimulation with cholescintigraphy (c)

fraction [137]. Three additional studies reported low gallbladder ejection fractions in about 15–25 % of normal controls [140, 144, 147, 191]. Gastrointestinal motility including gallbladder emptying can be affected by medication. For example, prior studies had already demonstrated the significant effect of anticholinergic agents or hormone replacement therapy in postmenopausal women on gallbladder contractions [158, 199]. Perhaps more importantly, a 30-day treatment with proton pump inhibitors, agents often given to patients with dyspeptic symptoms, significantly impaired gallbladder function with ejection fractions B35 % in 10 of 19 healthy volunteers [191]. Finally, exercise may affect the gallbladder by increasing meal-stimulated emptying [157]. Obviously, these results leave questions about a potentially significant prevalence of abnormal test results in asymptomatic individuals, in persons taking commonly prescribed medications, or in individuals starting or stopping an exercise program.

Defining Impaired Gallbladder Function in Patients As most studies reported data on patients who then underwent surgery, reproducibility could obviously not be

assessed in these cohorts. One study prospectively addressed this question and reexamined 44 symptomatic patients within 15 days of an abnormal initial test. While the averaged data remained stable over time, 10 (23 %) of the patients had results that fell within the normal range upon repeat assessment [141]. A second study retrospectively assessed patients followed for nearly 3 years without surgery [200]. Results generally correlated reasonably well over time. However, about 10 % of the patient controls, operationally defined as symptomatic individuals with normal gallbladder emptying, had one abnormal and about 25 % of biliary dyskinesia patients had one normal test result at one time point. It is unclear why a conservative approach was chosen and whether test results correlated with symptoms. The validation of a newly introduced test typically requires some reference or ‘‘gold standard’’ [201]. With the introduction of a new concept, namely impaired gallbladder contraction as a cause of disease, no standard was available, only allowing follow-up assessments as a surrogate measure to determine whether response to treatment segregates according to test results. Yet early on, test results were used to decide on treatment, limiting the ability to truly analyze performance characteristics. Only

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one small trial randomly allocated patients with abnormal tests to operative therapy or an expectant approach and reported better outcome after surgery [17]. However, the trial was designed to evaluate treatment, not testing for biliary dyskinesia. Moreover, the approach does not allow conclusions about the utility of abnormal ejection fraction diagnostic method as only one test outcome. With the increasing number of cholecystectomies for biliary dyskinesia, chronic inflammatory changes were often reported in the removed specimens (see below). While a microscopic gallbladder abnormality cannot serve as a ‘‘gold standard’’ for functional gallbladder testing in situ, one could view it as objective evidence of pathology that could perhaps function as an alternative definition of disease. Such an approach provides the disease-defining reference in the cohort of patients undergoing surgery, who lack controls. Nonetheless, one case series examined gallbladder emptying in patients undergoing cholecystectomy for chronic cholecystitis and did not find a significant difference compared to controls, arguing against a utility of functional gallbladder testing in identifying chronic cholecystitis [197]. Finally, validation of a newly introduced test, such as functional gallbladder testing, requires an assessment of findings in a relevant clinical population that is not highly enriched with individuals who have already been diagnosed with the disease investigated or who presumably have a disease defined by the very test that should be validated [202]. Thus, we need more than healthy controls as a reference standard as the test is supposed to differentiate biliary dyskinesia from other disorders with similar symptoms. Despite their small sample size, several studies of patient controls were published and raise further questions about the validity of biliary dyskinesia defined by impaired gallbladder emptying. Low gallbladder ejection fractions are seen in experimentally induced hyperglycemia and have been described in many other patient groups, such as patients with diabetes, celiac disease, prior foregut surgery or after spinal cord injury, various functional disorders of the gastrointestinal tract, or cirrhosis [148, 150, 151, 167, 170, 171, 173, 175, 176, 180, 181, 192, 193, 203–205]. While patients are by definition not asymptomatic, abnormal results were not related to the disease-defining symptoms described in expert reviews. Thus, the patients did not meet criteria for biliary dyskinesia as clinically relevant illness, but had ‘‘incidental’’ dyskinesia. The data do not suffice to truly estimate sensitivity or specificity of functional gallbladder testing in a relevant population. However, the presence of impaired gallbladder function in up to 20 % of asymptomatic individuals and an even higher number of abnormal tests in patients with various gastrointestinal or other disorders certainly leaves significant doubts whether

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Fig. 3 The scatter plot shows the reported improvement after cholecystectomy in patients with biliary symptoms but normal gallbladder ejection fraction (for citations see text)

assessment of gallbladder ejection fraction can reliably identify a distinct illness and/or discriminate between patient groups with different gastrointestinal disorders.

Functional Gallbladder Testing as Predictor of Treatment Response Despite the apparently unresolved questions about sensitivity, specificity, negative or positive predictive value of testing for biliary dyskinesia, the test could perhaps provide some prognostic information about the impact of treatment on patients. While most surgeons use the low gallbladder ejection fraction as diagnostic criterion, some patients underwent cholecystectomy purely based on symptoms despite an apparently normal gallbladder ejection fraction. Using these reports, we can thus address the impact of surgery in patients with normal and abnormal gallbladder function [9, 17, 49, 50, 59, 63, 67, 71, 73, 77, 78, 206, 207]. Adding these different case series, a total of 248 patients with normal gallbladder function were operated and followed for 27.1 ± 8.6 months with a reported 86.0 ± 3.2 % response rate (Fig. 3). These results do not differ from those seen in patients operated for documented biliary dyskinesia (see below). Thus, the available evidence does not support a utility of functional gallbladder testing as a prognostic marker.

Looking for a Surrogate: Chronic Acalculous Cholecystitis The increasing number of cholecystectomies in symptomatic individuals without cholelithiasis led to the description of chronic acalculous cholecystitis. As discussed above, such an approach is conceptually problematic, but could

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gallbladder testing. Beyond questions about the indication for surgery, the results will likely be skewed as gallbladder emptying was assessed prior to surgery and almost certainly played a role in treatment decisions. As already described previously, another study examined patient with chronic cholecystitis without excluding patients with cholelithiasis and did not see a significant difference in gallbladder emptying compared to controls [197].

Surgery for Biliary Dyskinesia: Patient Selection Fig. 4 The scatter plot shows the prevalence of chronic inflammation without stone disease in case series of patients undergoing cholecystectomy for biliary dyskinesia (black circles) or during bariatric or other abdominal surgeries (white squares) and in autopsy series (white circles)

perhaps add another biomarker to support the presence of a potentially relevant abnormality. Several case series report the prevalence of chronic inflammatory changes in gallbladders removed for biliary dyskinesia [9, 17, 39, 44, 45, 47, 48, 50, 52, 57–61, 63, 66, 68, 77, 206, 208–212]. As shown in Fig. 4, the rates of positive findings varied significantly with most studies reporting signs of chronic inflammation in about 80 % of the cases. Methodological details about the microscopic assessment of resection specimens were mostly lacking. Interestingly, a blinded review of cholecystectomy specimens confirmed the presence of chronic acalculous cholecystitis in less than half of the cases identified by the retrospective chart review [59]. Generating a scoring system or relying on morphometric data did not reveal differences between specimens removed for biliary dyskinesia and gallbladders obtained through ‘‘incidental’’ cholecystectomy [213]. Such incidental cholecystectomies are often performed in the context of bariatric surgery. Consistent with the two more detailed anatomic studies, chronic cholecystitis in the absence of stone disease has been reported in up to 90 % of gallbladders removed during gastric bypass or other abdominal surgeries [214–220]. Only two autopsy studies examined the presence of inflammatory changes in the gallbladder, showing chronic acalculous cholecystitis in none of 10 pediatric and 60.9 % of 50 adult cases [221, 222]. If chronic acalculous cholecystitis is indeed the morphologic correlate of biliary dyskinesia, then we should see impaired gallbladder function in patients with chronic acalculous cholecystitis. Despite the obvious caveat that cholecystectomy is needed to address this point, two case series described this relationship [172, 186]. While one study reported low gallbladder ejection fractions in the majority of patients, less than half of the cases in the second series had an abnormal result on functional

A total of 61 case series reported results of cholecystectomies for biliary dyskinesia and/or chronic acalculous cholecystitis. The information about the duration of symptoms prior to surgery was limited and variable. However, most surgeons apparently require some degree of chronicity with a mean symptom presence of 11 ± 2 months [22, 23, 42, 45, 46, 61–63, 65, 68, 77, 78, 210, 223, 224]. Consistent with the recommendation to exclude other diseases, patients typically undergo additional testing prior to cholecystectomy. However, most reports focused on evaluations of the biliary tree, typically with ultrasound and the assessment of the gallbladder ejection fraction [14, 17, 25, 34, 36, 40, 50, 57, 60, 63, 66, 77, 78, 225–228], while many other tests ranging from endoscopic evaluations to computerized tomography or magnetic resonance imaging were performed [14, 40, 50, 59, 225–227]. The decision to move toward cholecystectomy is typically made after completion of about three tests, which obviously includes structural and functional assessment of the gallbladder [36, 228]. Most surgeons use an ejection fraction of less than 40 % as their cutoff defining biliary dyskinesia [9, 14, 17, 22, 23, 34, 40, 42–46, 48–50, 52, 54, 57–63, 65–70, 72–74, 206, 210, 211, 223–230]. However, some rely on higher cutoffs [25, 39, 64, 71, 77, 78, 231] or less stringent criteria [11, 37, 38, 47, 51, 55, 56, 69, 75, 76]. As already described above, some patients undergo surgery based on symptoms alone, even if gallbladder testing was completely normal [9, 17, 49, 50, 59, 63, 67, 71, 73, 77, 78, 206, 207, 212].

Symptomatic Response to CCK Stimulation Considering the limited prognostic utility of functional gallbladder imaging [16], some authors suggested pain in response to CCK agonist infusion as a diagnostic criterion [206]. The alternative approach is based on two small case series showing signs of chronic cholecystitis in essentially all patients operated with high rates of postoperative satisfaction, prompting even the contradictory terminology of ‘‘normokinetic dyskinesia’’ [206, 232]. However,

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Fig. 6 Scatter plot showing the improvement rates in patients with abnormal gallbladder ejection fractions not undergoing cholecystectomy

Fig. 5 The scatter plot in a shows the reported response rates as a function of sample size based on published case series of biliary dyskinesia. The inset depicts the diagnostic criteria using gallbladdermeasured ejection fractions (see text for details). b Correlates improvement rates with follow-up time (r2 = -0.31)

additional reports commented on agonist-evoked pain in 20–40 % of their cohort [59, 61, 65]. Prospective studies are lacking, and investigations in healthy volunteers or disease controls are still missing. However, the pain triggered by CCK stimulation did not correlate with symptomatic responses or future resource utilization [61, 233, 234]. Considering the widespread expression of CCK receptors and the potential role of CCK in other disorders including irritable bowel syndrome, it is unlikely that symptomatic response alone will appropriately differentiate biliary from other diseases [235].

Surgery for Biliary Dyskinesia: Outcome Except for a single randomized controlled trial [17], all publications report the outcome of consecutively operated patients based on retrospective reviews of recorded data. The outcome assessment typically relies on some postoperative contact with previously operated individuals, asking them to rate symptoms. This was mostly using verbal descriptors, such as resolved, improved, stable, or worse. After a mean postoperative follow-up of 20.9 ± 2.0 months, most surgeons published success rates of about 80 % (Fig. 5a). These findings are identical to those obtained in patients with normal gallbladder ejection fraction undergoing cholecystectomy (Fig. 3). Improvement rates significantly decrease with longer follow-up

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(Fig. 5b). In patients with gallstone disease, pain rather than vague dyspeptic symptoms is more likely to respond to cholecystectomy [5]. Similar data for biliary dyskinesia are missing. It is certainly possible that a more differentiated assessment of symptoms may provide better insight into preoperative parameters that provide better prognostic information.

Natural History of Biliary Dyskinesia How do these data compare to the natural history of this disease? In the absence of any truly observational study, we can certainly not describe the natural history of biliary dyskinesia. However, we should keep the mostly benign course of gallstone disease in mind [136]. At least some information can be obtained from studies describing the outcome of patients with documented biliary dyskinesia who did not undergo cholecystectomy. Only one group randomly allocated patients to surgery or wait-listing [17], while none of the remaining reports provided sufficient details about therapeutic decision-making criteria and/or nonoperative therapies [9, 14, 51, 52, 57, 59, 60, 63, 69, 70, 72, 77, 78, 226, 229, 231]. As shown in Fig. 6, response rates were lower and variable with an average around 50 %. Interestingly, only the randomized trial did not show any improvement in wait-listed patients, which is very different from published data in functional gastrointestinal disorders, raising questions about the validity of the control arm in this trial. Despite these shortcomings, the overall findings do show high improvement rate even without any specific active therapy. Only one small trial in children systematically assessed and treated patients with documented biliary dyskinesia for possible reflux disease and noted symptomatic improvement in nearly 60 % within weeks [236].

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Biliary Dyskinesia: Time for a New Direction Early on, physicians recognized the challenge of biliary symptoms in the absence of stone disease. More than 20 years ago, clinical investigators and practitioners turned to functional testing. While the assessment of gallbladder emptying was rapidly adopted as diagnostic tool, we still lack convincing evidence that impaired gallbladder contraction truly explains this scenario. Nonetheless, surgery for biliary dyskinesia remains common and may even be on the rise with more ambulatory surgeries being performed in low-risk patients. The discrepancy between expert consensus, defining biliary dyskinesia as a rare disorder, and the common surgical practice of cholecystectomy in the absence of stone disease, highlights the need for systematic investigations to address a few key questions. Is biliary dyskinesia truly a motor disorder that selectively affects the biliary tree? While systematic evidence is lacking, physicians may focus on the gallbladder that can be removed with relative ease and a low likelihood of complications, even though the impaired gallbladder function may simply be a surrogate for more widespread functional changes, as suggested by our recent finding of high cholecystectomy rates in patients with gastroparesis [232]. Similarly, patients with irritable bowel syndrome have a threefold risk of undergoing cholecystectomy compared to matched controls [233]. Pain, nausea, and other common symptoms of biliary dyskinesia overlap with several other structural and functional disorders of the gastrointestinal tract. Such disorders do not only overlap, but they may also resolve or evolve into other functional disorders characterized by pain [234]. At this point, the benign course and natural history of other functional illnesses, such as functional dyspepsia, irritable bowel syndrome, or gastroparesis, argue against drastic interventions, such as surgery, which should certainly caution us when contemplating surgery for biliary dyskinesia. If biliary dyskinesia truly is a selective motor disorder of the biliary tree, can we use active medical therapy rather than surgery to treat this disease? Small studies clearly demonstrated changes in gallbladder ejection fraction with medical therapy [163, 170, 235, 236]. These studies were largely proof of concept investigations. They were not conducted over sufficiently long time period and did not address the potential impact on symptoms. Yet, they established that one of the defining criteria of biliary dyskinesia could be addressed with nonoperative interventions. Considering our understanding of other functional diseases, we need to ask whether biliary dyskinesia is truly a motility disorder. Clinical studies in other diseases have demonstrated that abnormal motor patterns or changes in transit do not closely correlate with symptoms [237, 238].

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More detailed investigations of sphincter of Oddi dysfunction suggested a significant contribution of visceral hypersensitivity in this disorder defined by impaired motility of the biliary sphincter [239]. Could hypersensitivity or hypervigilance similarly contribute to the symptoms in patients with decreased gallbladder ejection fraction? Pain as the predominant symptom in biliary dyskinesia will likely be influenced by many different phenomena, including affect. Interestingly, trait anxiety significantly influenced the outcome after cholecystectomy for gallstone disease [240]. While this information is finding its way into the assessment of symptomatic cholelithiasis, no study has addressed the role of sensory or cognitive mechanisms in patients with presumed biliary dyskinesia. Cholecystectomy is increasingly done as outpatient surgery and carries low morbidity and very low mortality rates. Nonetheless, bile duct injuries occur in up to 4 % of patients, a number that will likely be lower in the relatively young and otherwise healthy persons diagnosed with biliary dyskinesia. With the gaps in knowledge, we need to fill these gaps in knowledge by obtaining more comprehensive information about gastrointestinal structure and function in our patients with presumed biliary dyskinesia. We should examine the role of psychological factors, enroll patients into trials that offer more than just wait-listing as the alternative to an active therapy, develop and test treatments that address some of the underlying mechanisms rather than removing the gallbladder. To conclude, we feel that the available data are of low quality for a definitive role of surgery in biliary dyskinesia. More than two decades after the only randomized controlled trials in biliary dyskinesia [17], it is time to design and conduct a trial that compares active treatment arms and will hopefully provide more convincing answers. Conflict of interest

None.

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