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INTRODUCTION — Functional gallbladder disorder is defined as biliary pain resulting from a primary gallbladder motility disturbance in the absence of gallstones, sludge, microlithiasis, or microcrystal disease. The diagnosis is considered in patients with typical biliary-type pain who have had other causes for the pain excluded. The prevalence of functional gallbladder disorder among patients with biliary-type pain and a normal transabdominal gallbladder ultrasound is up to 8 percent in men and 21 percent in women [1-3].
In the past, functional gallbladder disorder has been referred to by various names, including gallbladder dyskinesia, gallbladder spasm, acalculous biliary disease, chronic acalculous cholecystitis, chronic acalculous gallbladder dysfunction, and cystic duct syndrome.
This topic will review the clinical manifestations, diagnosis, and treatment of patients with suspected functional gallbladder disorder. The approach to patients with other causes of biliary-type pain, including gallstones or suspected sphincter of Oddi dysfunction, is discussed separately. (See "Approach to the patient with incidental gallstones" and "Uncomplicated gallstone disease in adults" and "Clinical manifestations and diagnosis of sphincter of Oddi dysfunction" and "Treatment of sphincter of Oddi dysfunction".)
PATHOGENESIS — The etiology of functional gallbladder disorder is unclear, but it is generally regarded as a motility disorder of the gallbladder. It may result from an initial metabolic disorder (ie, bile supersaturated with cholesterol) or a primary motility disorder in the absence, at least initially, of any abnormalities of bile composition [4,5]. It has been noted that patients with functional gallbladder disorder may have abnormal gastric emptying and colonic transit, suggesting a possible generalized gastrointestinal motility disorder . The hypothesis that functional gallbladder disorder is related to abnormal gallbladder motility is the basis for measuring the gallbladder ejection fraction as part of the evaluation. (See 'CCK-stimulated cholescintigraphy' below.)
CLINICAL MANIFESTATIONS — Patients with functional gallbladder disorder present with biliary-type pain, also known as biliary colic. Their liver and pancreas blood tests are normal, no gallstones or gallbladder sludge are seen on imaging, and upper endoscopic examinations are normal. (See 'Exclude gallstones' below.)
Biliary-type pain — Biliary-type pain is typically caused by cholelithiasis, sludge, microlithiasis, or microcrystal disease, but it can also be a manifestation of functional gallbladder disorder, sphincter of Oddi dysfunction, or common bile duct stones. Despite the name, biliary colic is usually constant and not colicky. The classic description is of an intense discomfort located in the right upper quadrant or epigastrium that may radiate to the back (particularly the right shoulder blade). The pain is often associated with diaphoresis, nausea, and vomiting. The pain plateaus in less than an hour, ranging from moderate to excruciating in severity. Once it has plateaued, the pain typically lasts at least 30 minutes and then slowly subsides over several hours, with the entire attack usually lasting less than six hours. (See "Uncomplicated gallstone disease in adults", section on 'Biliary colic'.)
While biliary-type pain often develops one to two hours after ingestion of a fatty meal, an association with meals is not universal, and in a significant proportion of patients the pain is nocturnal, with a peak occurrence around midnight [7,8].
In most cases, the pain has a characteristic pattern and timing for an individual patient. While the pain is recurrent, it occurs at variable intervals (not daily). After an attack, the physical examination is usually normal, with the possible exception of residual upper abdominal tenderness. While nonspecific dyspeptic symptoms, such as indigestion, abdominal bloating, and belching, may coexist in patients with biliary colic, they are not usually relieved by cholecystectomy. As a result, these symptoms are thought to be due to causes other than a gallbladder disorder .
Laboratory, imaging, and endoscopic studies — Patients with functional gallbladder disorder have normal blood tests, including aminotransferases, bilirubin, alkaline phosphatase/gamma-glutamyl transpeptidase, amylase, and lipase . In addition, abdominal imaging is normal, with no evidence of gallstones, gallbladder sludge, or cholesterol polyps. Finally, patients have normal upper endoscopic examinations.
DIAGNOSIS — Functional gallbladder disorder is a diagnosis of exclusion in a patient with typical biliary-type pain. The first step in the evaluation of such patients is to exclude other causes for the patient's pain. If no other causes are identified, patients should undergo cholecystokinin (CCK)-stimulated cholescintigraphy to confirm the diagnosis. CCK-stimulated cholescintigraphy allows for calculation of the gallbladder ejection fraction (GBEF), which is low in patients with functional gallbladder disorder (<40 percent) and helps predict which patients are likely to respond to cholecystectomy. (See 'CCK-stimulated cholescintigraphy' below and 'Patient selection for cholecystectomy' below.)
However, while the GBEF is a component of consensus guidelines for diagnosing functional gallbladder disorder, many of the studies supporting the use of the GBEF for diagnosis are of poor methodologic quality and are not conclusive. Therefore, it is imperative that patients have a careful history obtained and that functional gallbladder disorder only be considered if typical biliary-type pain is present. The presence of typical biliary-type pain is the best predictor of a response to cholecystectomy in patients with a low GBEF . In addition, some patients with normal gallbladder emptying and biliary-type pain also benefit from surgery. (See 'Patient selection for cholecystectomy' below.)
Clinical criteria — Consensus guidelines (the Rome IV criteria) have been developed to help diagnose functional gallbladder disorder . Patients who fulfill these criteria should undergo an evaluation for functional gallbladder disorder, whereas patients who do not fulfill all of the criteria should be evaluated for alternative causes of their abdominal pain. (See "Evaluation of the adult with abdominal pain".)
Rome IV criteria for functional gallbladder disorder require:
●Absence of gallstones or other structural pathology
In addition, the criteria that are supportive of functional gallbladder disorder, but are not required, include:
●Low ejection fraction on scintigraphy
●Normal liver enzymes, conjugated bilirubin, and amylase/lipase
To fulfill the Rome IV criteria for biliary-type pain, patients need to have pain that:
●Is located in the epigastrium and/or right upper quadrant
●Occurs at variable intervals (not daily)
●Lasts at least 30 minutes
●Builds up to a steady level
●Is severe enough to interrupt daily activities or lead to an emergency department visit
●Is not significantly (<20 percent) relieved by bowel movements, postural changes, or acid suppression
Criteria that are supportive of biliary pain, but are not required, include: (a) pain that is associated with nausea and vomiting, (b) pain that radiates to the back and/or right subscapular region, and (c) pain that awakens the patient from sleep in the middle of the night.
The Rome IV criteria help clinicians identify patients with typical biliary-type pain. We strongly believe that taking a careful history with a detailed description of the painful attacks is essential to identify patients with typical biliary attacks and that patients only be considered for further testing with CCK-stimulated cholescintigraphy if they have typical biliary-type pain and other possible causes of the pain have been excluded.
Exclude other diagnoses — In patients with biliary-type pain, the evaluation begins with basic laboratory tests and a transabdominal ultrasound looking for gallstones or gallbladder sludge. If the transabdominal ultrasound is negative, it should be followed by EUS and bile microscopy to exclude small stones and microcrystal disease. If the evaluation for stones and microcrystal disease is negative, evaluation for other disorders in the differential diagnosis of biliary-type pain, including acid-peptic disease, ischemic heart disease, and functional gallbladder disorder should be pursued.
Laboratory tests — Blood tests should be obtained to look for evidence of liver disease, biliary obstruction, and pancreatitis. These tests include serum alanine aminotransferase, aspartate aminotransferase, bilirubin, alkaline phosphatase/gamma-glutamyl transpeptidase, amylase, and lipase. (See "Approach to the patient with abnormal liver biochemical and function tests" and "Clinical manifestations and diagnosis of acute pancreatitis", section on 'Pancreatic enzymes and products'.)
Exclude gallstones — Typically, a transabdominal ultrasound is the first imaging test obtained in patients with biliary-type pain [4,12]. Transabdominal ultrasound is noninvasive and does not expose patients to ionizing radiation. Patients should fast for eight hours prior to the ultrasound to allow for distension of the gallbladder, which permits better visualization of gallstones and sludge.
Sludge is an ultrasound diagnosis of echogenic layering in the gallbladder that does not cast an acoustic shadow (image 1). Biliary sludge is composed of cholesterol microcrystals embedded in a mucous gel and pigment . Patients may also have a finding of "gravel" on ultrasound. Gravel is made up of small stones that may be beyond the resolution of ultrasound but that cast an acoustic shadow. The presence of sludge or gravel is as significant as the finding of stones in a patient with biliary type pain and is a clear indication for cholecystectomy in these patients. The same can be said about cholesterol polyps as these can detach and obstruct the cystic duct and the common bile duct, leading to biliary pain, cholecystitis, or pancreatitis. (See "Uncomplicated gallstone disease in adults", section on 'Characteristics of stones on ultrasound' and "Gallbladder polyps and cholesterolosis".)
If the initial transabdominal ultrasound is negative in a patient with typical biliary-type pain, a repeat examination should be obtained, with special attention being paid to commonly overlooked areas (eg, Hartmann's pouch or Phrygian cap, if present). If the repeat transabdominal ultrasound is still negative, additional testing may include an endoscopic ultrasound (EUS) to detect small stones that are beyond the resolution of transabdominal ultrasound. If EUS is negative, bile microscopy is performed to look for microlithiasis or microcrystal disease. We consider microlithiasis to be a synonym for microcrystal disease that can be diagnosed only with bile microscopy, although some authors refer to microlithiasis as small stones less than 3 mm in diameter that can be diagnosed with endoscopic ultrasound.
A detailed approach to the diagnosis of gallstones is presented elsewhere. (See "Uncomplicated gallstone disease in adults", section on 'Diagnosis'.)
Exclude other disorders — Patients with a negative evaluation for gallstones or sludge should be evaluated for other disorders in the differential diagnosis of biliary-type pain. This typically includes an evaluation for acid-peptic disease, consideration of functional dyspepsia, and evaluating for ischemic heart disease when indicated.
Additional testing for disorders such as sphincter of Oddi dysfunction or chronic pancreatitis will depend upon the patient's history, symptoms, laboratory test findings, and imaging test results. Patients with sphincter of Oddi dysfunction often have elevated liver tests and a dilated bile duct. (See "Uncomplicated gallstone disease in adults", section on 'Differential diagnosis' and "Clinical manifestations and diagnosis of sphincter of Oddi dysfunction".)
Ischemic heart disease — Coronary artery disease, particularly inferior wall ischemia, may present as upper abdominal discomfort. Typically, this type of discomfort differs from biliary-type pain in that it is effort induced, radiates to the chest or left shoulder, and has a sudden onset. Clinicians should have a low threshold for initiating a cardiac evaluation, particularly in patients with risk factors for coronary artery disease or with other symptoms suggestive of cardiac disease. (See "Outpatient evaluation of the adult with chest pain".)
Acid-peptic disease — Patients with acid-peptic disease (peptic ulcer disease, gastroesophageal reflux disease) or functional dyspepsia may resemble patients with biliary disease. Patients with acid-peptic disease or functional dyspepsia may report burning pain in the epigastric area (dyspeptic pain) that occurs when fasting, two to four hours after a meal, or at night on an empty stomach.
While dyspeptic pain may resemble biliary-type pain, dyspeptic pain is typically less severe and rarely results in a visit to the emergency room. In addition, dyspeptic pain is usually more prolonged and frequent than biliary-type pain, and often occurs on a daily basis. Unlike biliary-type pain, dyspeptic pain may be relieved by food or antacids. However, while a response to antacids is common in patients with peptic ulcer disease or acid reflux, the response is variable in patients with functional dyspepsia. (See "Approach to the adult with dyspepsia" and 'Functional dyspepsia' below.)
The approach to patients with dyspeptic pain depends upon the patient's age and associated symptoms. A trial of empiric antacid therapy is reasonable for younger patients with typical dyspeptic symptoms since upper endoscopy is generally of low yield in such patients. However, endoscopy is recommended for patients older than 45 years of age, those with "alarm symptoms" such as weight loss or anemia, and those who fail 10 to 14 days of empiric therapy. An upper endoscopy can be done during the same endoscopic session as EUS. (See "Approach to the adult with dyspepsia", section on 'Diagnostic strategies and initial management'.)
Functional dyspepsia — Like functional gallbladder disorder, functional dyspepsia is a diagnosis of exclusion, so prior to making either diagnosis, patients require a thorough evaluation. Once other disorders have been excluded, differentiating patients with functional gallbladder disorder from those with functional dyspepsia depends upon the character of the patient's symptoms. Unlike biliary pain, functional dyspepsia is usually described as a mild pain that is continuous or occurs daily and lasts for more than six hours. Functional dyspepsia is often associated with bloating and immediate worsening with meals. In patients with symptoms suggestive of functional dyspepsia, additional testing for functional gallbladder disorder is not indicated. (See "Approach to the adult with dyspepsia" and 'Exclude gallstones' above.)
If patients have typical biliary-type pain, the disorders are differentiated based upon the results of CCK-stimulated cholescintigraphy, with a low gallbladder ejection fraction (<40 percent) making a diagnosis of functional gallbladder disorder more likely. (See 'CCK-stimulated cholescintigraphy' below and 'Management' below.)
CCK-stimulated cholescintigraphy — CCK-stimulated cholescintigraphy is used to estimate the gallbladder ejection fraction (GBEF). Patients with a GBEF of less than 35 to 40 percent are considered to have abnormal gallbladder motility and are more likely to respond to cholecystectomy [14,15]. CCK-stimulated cholescintigraphy should only be performed in patients with typical biliary symptoms. It should not be ordered for atypical symptoms such as bloating, fullness, or dyspeptic symptoms, as these patients are unlikely to respond to surgery even in the presence of a low GBEF . (See 'Patient selection for cholecystectomy' below.)
Following an overnight fast, 99mTc-diisopropyl-iminodiacetic acid (DISIDA) or 99mTc-hepatic iminodiacetic acid (HIDA) is given as an intravenous bolus. The radiolabeled tracer is excreted in the bile, and if the cystic duct is patent, it will flow into the gallbladder. After 45 to 90 minutes, baseline radioactivity from the region of the gallbladder is measured. When the radioactivity is maximal from the gallbladder and is minimal from the liver, an infusion of CCK is started to stimulate gallbladder contraction, which leads to expulsion of the radiolabeled tracer. CCK-stimulated cholescintigraphy should be performed with a slow infusion of CCK (sincalide 0.02 mcg/kg given over 30 to 60 minutes) . Rapid administration of CCK (over two to three minutes) is associated with cramping, patient discomfort, and highly variable results . Slower infusion rates (over 30 to 60 minutes) lead to less inter- and intra-subject variability and an overall increase in mean gallbladder ejection fraction compared with rapid infusion [17-19]. Variability in CCK administration techniques may account for some of the differences seen in studies examining the ability of the GBEF to predict a response to cholecystectomy. (See 'Patient selection for cholecystectomy' below.)
Following CCK infusion, the radioactivity in the region of the gallbladder is again measured and subtracted from the baseline activity (image 2).
The GBEF is then calculated using the formula:
GBEF = (baseline activity – activity after CCK infusion)/baseline activity
Multiple medications and medical conditions other than functional gallbladder disorder are associated with decreased gallbladder emptying and should be kept in mind when interpreting CCK-stimulated cholescintigraphy results [10,20,21]. False-positive results can be seen with diabetes, celiac disease, obesity, cirrhosis, and several medications, including calcium channel blockers, oral contraceptives/progesterone, histamine-2 receptor antagonists, opiates, benzodiazepines, atropine, octreotide, and theophylline.
A systematic review attempted to evaluate the usefulness of GBEF for determining which patients with suspected functional gallbladder disorder are likely to respond to cholecystectomy (thus making a diagnosis of functional gallbladder disorder more likely). It included 23 studies with 1718 patients with suspected functional gallbladder disorder . Nineteen of the studies concluded that calculation of a GBEF was useful in predicting a response to cholecystectomy in patients with suspected functional gallbladder disorder. However, the authors noted that all of the studies were of poor methodologic quality, which precluded a meta-analysis. All but three of the studies were retrospective case series, only one was randomized, and no study was adequately blinded.
As an example, one study that suggested GBEF is useful for predicting a response to cholecystectomy retrospectively analyzed 345 patients with biliary-type pain ; 195 patients had a low GBEF (<35 percent) and 150 had a normal GBEF (≥35 percent). Among those with a low GBEF, 110 of 113 patients (97 percent) treated with surgery had symptom improvement, compared with 13 of 82 (16 percent) who were managed medically for non-gallbladder disease. Conversely, patients with normal GBEFs did well with medical management for non-gallbladder disease, with 130 of 139 patients (94 percent) reporting improvement. Finally, patients with normal GBEFs who were referred for surgery also did well (10 of 11 had symptom improvement), though it is not clear from the study what lead to the patients being referred for surgery. Thus, this study suggests that surgical therapy is appropriate for patients with a low GBEF and that medical therapy is appropriate for those with a normal GBEF. However, the study is limited by the fact that it is retrospective, leading to potential biases regarding which patients were referred for surgery.
DIFFERENTIAL DIAGNOSIS — The primary considerations in the differential diagnosis of functional gallbladder disorder are gallstones and gallbladder sludge, which are more common causes of biliary-type pain. Gallstones and sludge are typically identified on transabdominal ultrasound, though in some cases endoscopic ultrasound or biliary microscopy may be required. Cholesterol polyps are another cause for biliary pain that can be diagnosed with ultrasound. (See 'Exclude gallstones' above and "Gallbladder polyps and cholesterolosis".)
Other considerations in the differential diagnosis include sphincter of Oddi dysfunction and non-biliary causes of abdominal pain, such as functional dyspepsia. (See 'Exclude other disorders' above.)
MANAGEMENT — Cholecystectomy is the treatment for functional gallbladder disorder. Patients are candidates for cholecystectomy if they fulfill the clinical criteria for functional gallbladder disorder, if alternative explanations for their symptoms have been excluded, and if their gallbladder ejection fraction (GBEF) is reduced (<40 percent). Patients who develop pain during cholecystokinin infusion may be particularly likely to respond well to cholecystectomy, though it is important that the cholecystokinin be administered properly, as rapid administration could result in cramping that may be confused with the patient's biliary-type pain. Alternative therapies, such as bile acid composition modifiers, promotility agents, and anti-inflammatory drugs, have not been adequately studied . (See "Laparoscopic cholecystectomy" and "Open cholecystectomy" and 'CCK-stimulated cholescintigraphy' above.)
The benefit of cholecystectomy over nonsurgical management was demonstrated in a meta-analysis that included 10 studies with a total of 615 patients with right upper quadrant pain, no gallstones, and a positive cholecystokinin (CCK)-stimulated hepatic iminodiacetic acid (HIDA) scan. It found that cholecystectomy was more likely than medical therapy to achieve complete symptom relief in patients with a low GBEF (odds ratio 16.3) . However, the included studies had numerous limitations, including lack of blinding, nonrandomized designs, variable lengths of follow-up, non-standardized protocols for determining the GBEF, non-standardized methods of assessing clinical outcomes, and poor follow-up of dropouts.
Patient selection for cholecystectomy — Patients with functional gallbladder disorder are candidates for cholecystectomy if they have typical biliary-type pain and a low GBEF (<40 percent). While studies suggest that such patients are likely to benefit from cholecystectomy, most of the studies showing an association of a low GBEF with improved outcomes are retrospective, and GBEF has not conclusively been proven to be a reliable indicator of clinical outcome. However, while imperfect, it is the most studied predictor of whether a patient will respond to cholecystectomy. (See 'CCK-stimulated cholescintigraphy' above.)
There is uncontrolled observational evidence that the recreation of a patient's typical biliary-type pain during CCK infusion (CCK provocation) may predict a response to cholecystectomy, regardless of GBEF [11,26-28]. In a series of 42 patients undergoing cholecystectomy for biliary-type pain and no gallstones, 17 had a GBEF of <35 percent and 25 had a GBEF of ≥35 percent . All of the patients had recreation of their pain during CCK infusion. Despite the normal GBEF in 25 patients, all 42 patients had symptom resolution following cholecystectomy, and only one patient had recurrent symptoms after a mean follow-up of 19 months.
We do not generally base surgical decisions based upon CCK provocation of abdominal pain because of variability in describing pain and the subjective nature of this test. However, the recreation of typical biliary-type pain during CCK-stimulated cholescintigraphy may be supportive of the diagnosis, and rarely we will refer a patient with CCK-provoked biliary-type pain and a normal GBEF for cholecystectomy, provided treatments for other disorders (eg, acid suppressive therapy) have failed. However, we must stress that many times the infusion of CCK will lead to abdominal cramping, especially in the case of rapid infusion. Cramping due to the CCK infusion must not be confused with recreation of the patient's biliary-type pain.
SUMMARY AND RECOMMENDATIONS
●Functional gallbladder disorder is a diagnosis that is considered in patients with typical biliary-type pain who do not have gallstones or gallbladder sludge. It is a diagnosis of exclusion, and the symptoms associated with functional gallbladder disorder may also be seen in patients with various disorders, including gallstone disease, peptic ulcer disease, ischemic heart disease, and functional dyspepsia. (See 'Clinical manifestations' above and 'Differential diagnosis' above.)
●To make a diagnosis of functional gallbladder disorder, specific clinical criteria should be met, and other causes for the patient's pain need to be ruled out. Cholecystokinin-stimulated cholescintigraphy is then performed to identify patients who may respond to cholecystectomy. (See 'Diagnosis' above.)
●Our general approach to patients who meet criteria for typical biliary-type pain is as follows (see 'Clinical criteria' above):
•Obtain liver and pancreas blood tests to look for evidence of biliary obstruction or pancreatitis. (See "Choledocholithiasis: Clinical manifestations, diagnosis, and management" and "Clinical manifestations and diagnosis of acute pancreatitis".)
•Exclude gallstones, sludge, cholesterol polyps, and microcrystal disease. (See 'Exclude gallstones' above.)
If the evaluation for these biliary sources of pain is negative, consider other disorders in the differential diagnosis of biliary-type pain. This typically includes evaluating for acid-peptic disease, functional dyspepsia, and ischemic heart disease when indicated. Additional testing for disorders such as sphincter of Oddi dysfunction or chronic pancreatitis will depend upon the patient's history, symptoms, laboratory test findings, and imaging test results. (See 'Exclude other diagnoses' above and "Uncomplicated gallstone disease in adults", section on 'Differential diagnosis'.)
●If other disorders are excluded in a patient with typical biliary-type pain, perform CCK-stimulated cholescintigraphy to calculate the gallbladder ejection fraction. Patients with atypical symptoms such as bloating, fullness, or dyspeptic symptoms, are generally treated for functional dyspepsia and should not undergo CCK-stimulated cholescintigraphy. (See 'CCK-stimulated cholescintigraphy' above and "Functional dyspepsia in adults".)
●If the gallbladder ejection fraction is <40 percent and there are no other conditions associated with reduced gallbladder emptying, the diagnosis of functional gallbladder disorder is possible, and treatment for functional gallbladder disorder is reasonable. The diagnosis can only be confirmed if the patient responds to treatment. (See 'Management' above.)
•We suggest that patients with suspected functional gallbladder disorder following an appropriate evaluation be treated with cholecystectomy rather than medical management (Grade 2B). Patients with atypical symptoms or a normal gallbladder ejection fraction are less likely to respond to treatment and should be reassessed for alternative causes of their symptoms. We will rarely consider cholecystectomy in patients with typical biliary-type pain and a normal gallbladder ejection fraction, provided no other likely diagnoses have been identified, empiric treatments for other disorders (eg, acid suppressive therapy) have failed, and the pain is reproduced with a properly administered CCK infusion. (See 'Patient selection for cholecystectomy' above.)
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