Functional gallbladder disorder in adults

INTRODUCTION — Functional gallbladder disorder is characterized by biliary pain in the absence of gallstones, sludge, microlithiasis, or microcrystal disease. The diagnosis requires an evaluation to exclude other organic causes of pain. Previously referred to as gallbladder dyskinesia, gallbladder spasm, acalculous biliary disease, chronic acalculous cholecystitis, chronic acalculous gallbladder dysfunction, or cystic duct syndrome; functional gallbladder disorder results from a gallbladder dysmotility.

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 management of gallstones" and "Overview of gallstone disease in adults".)

EPIDEMIOLOGY — Functional gallbladder disorder is rare as compared with other functional gastrointestinal disorders [1]. In a cross-sectional survey completed by 5931 of 6300 adults, 2083 (35 percent) had symptoms compatible with a functional gastrointestinal disorder as defined by the Rome IV criteria [1]. Only 10 (0.2 percent) individuals met the defined criteria for functional gallbladder disorder. Functional gallbladder disorder is a common indication for surgery and accounts for 2 to 5 percent in adults and up to 10 percent in children [2-4].

PATHOGENESIS — The etiology of functional gallbladder disorder is unclear, but gallbladder dysmotility is hypothesized to play a central role in the pathogenesis. Gallbladder dysmotility may result from an initial metabolic disorder (ie, bile supersaturated with cholesterol) which increases bile viscosity or a primary motility disorder in the absence, at least initially, of any abnormalities of bile composition [5,6]. Functional gallbladder disorder has been associated with abnormal gastric emptying and colonic transit, suggesting a possible generalized gastrointestinal motility disorder [7]. One study showed significant increase in mast cell infiltration and activation in the muscular wall of gallbladders compared to the controls, suggesting possible involvement of mast cells in gallbladder dysmotility in patients with functional gallbladder disease [8].

CLINICAL MANIFESTATIONS

Biliary-type pain — Patients with functional gallbladder disorder present with biliary-type pain (biliary colic). Despite the name, biliary colic is usually constant and not colicky. The classic description of biliary pain is 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 "Overview of 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 [9,10]. 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 and usually not daily. Biliary pain is not specific for functional gallbladder disorder and is typically caused by cholelithiasis, sludge, microlithiasis, or microcrystal disease, but it can also be a manifestation of sphincter of Oddi dysfunction, or common bile duct stones. (See 'Differential diagnosis' below.)

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 [11].

Laboratory tests and abdominal imaging — Patients with functional gallbladder disorder have normal blood tests, including aminotransferases, bilirubin, alkaline phosphatase/gamma-glutamyl transpeptidase, amylase, and lipase [12]. In addition, abdominal imaging is normal, with no evidence of gallstones, gallbladder sludge, or cholesterol polyps.

DIAGNOSIS

Overall approach — Functional gallbladder disorder is a diagnosis of exclusion in a patient with typical biliary-type pain. A clinical diagnosis of functional gallbladder disorder requires the fulfillment of symptom-based diagnostic criteria and an evaluation to exclude underlying organic disease. (See 'Diagnostic criteria' below.)

In patients with biliary-type pain, the evaluation begins with basic laboratory tests and a transabdominal ultrasound for gallstones or gallbladder sludge. If the initial abdominal ultrasound is negative, a repeat ultrasound should be performed, with special attention to commonly overlooked areas (eg, gallbladder infundibulum or Hartmann's pouch and Phrygian cap, if present) [5]. In patients with a normal abdominal ultrasound, we perform upper endoscopy and endoscopic ultrasound (EUS) to exclude acid peptic disease and small stones, respectively. In patients with a negative EUS, we perform bile microscopy for microcrystal disease. An additional evaluation may be needed in selected cases based on the clinical presentation. (See 'Initial evaluation to rule out alternative diagnoses' below.)

In the absence of gallstones or other organic causes of biliary pain, we perform cholecystokinin (CCK)-stimulated cholescintigraphy to evaluate the gallbladder ejection fraction (GBEF). A low GBEF is supportive of the diagnosis of functional gallbladder disorder but is not required to establish the diagnosis and is not specific for the diagnosis when abnormal. (See 'Assessment of gallbladder emptying' below.)

Diagnostic criteria — Symptom-based criteria (Rome IV) have been proposed to standardize the diagnosis of functional gallbladder disorder [5]. Patients who fulfill these criteria should undergo an evaluation for functional gallbladder disorder, whereas patients who do not fulfill 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:

●Biliary pain – Biliary pain is defined as pain in the epigastrium and/or right upper quadrant that meets all of the following criteria:

•Builds up to a steady level and lasts at least 30 minutes

•Occurs at different intervals (usually not daily)

•Is severe enough to interrupt daily activities or lead to an emergency department visit

•Is not significantly (<20 percent) related to bowel movements or relieved by postural change, or acid suppression

Criteria that are supportive of biliary pain, but are not required, include: pain that is associated with nausea and vomiting, radiation of pain to the back and/or right infrascapular region, and pain that awakens the patient from sleep.

●Absence of gallstones or other structural pathology

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

Initial evaluation to rule out alternative diagnoses

History — We perform a thorough history with particular attention to the symptoms that are concerning for organic disease. As examples:

●Radiation of pain to the back or personal or family history of pancreatitis may be indicative of underlying chronic pancreatitis.

●Significant weight loss, anorexia, vomiting, dysphagia, odynophagia, and a family history of gastrointestinal cancers suggest the presence of an underlying gastroesophageal malignancy. (See "Clinical features, diagnosis, and staging of gastric cancer", section on 'Clinical features'.)

●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. (See "Functional dyspepsia in adults", section on 'Clinical manifestations'.)

Laboratory tests — Blood tests should be performed to identify patients with liver disease, biliary obstruction, and pancreatitis. These tests include serum alanine aminotransferase, aspartate aminotransferase, bilirubin, alkaline phosphatase, 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'.)

Abdominal ultrasound — A transabdominal ultrasound is the first imaging test obtained in patients with biliary-type pain [5,13]. 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 (image 1). (See "Gallbladder polyps" and "Overview of gallstone disease in adults", section on 'Transabdominal ultrasound'.)

Upper endoscopy, EUS, and bile microscopy — EUS can detect small stones that are beyond the resolution of transabdominal ultrasound, small pancreatic tumors, and subtle changes of chronic pancreatitis. An upper endoscopy can be performed during the same endoscopic session as the EUS to rule out peptic ulcer disease as an alternative cause of abdominal pain. (See 'Differential diagnosis' below and "Peptic ulcer disease: Clinical manifestations and diagnosis", section on 'Upper endoscopy'.)

If upper endoscopy and EUS are negative, bile microscopy may be performed to look for microlithiasis/microcrystal disease. A detailed approach to the diagnosis of gallstones is presented elsewhere. (See "Overview of gallstone disease in adults", section on 'Evaluation for uncomplicated gallstone disease'.)

Additional tests in selected patients — 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. (See "Overview of gallstone disease in adults", section on 'Differential diagnosis' and 'Differential diagnosis' below.)

Assessment of gallbladder emptying

CCK-stimulated cholescintigraphy — CCK-stimulated cholescintigraphy is used to estimate the gallbladder ejection fraction (GBEF) to support the diagnosis of functional gallbladder disorder and to select patients who may benefit from cholecystectomy. A GBEF of less than 35 to 40 percent is considered low. Low ejection fraction on scintigraphy is supportive but not diagnostic of functional gallbladder disorder as the predictive value of a low GBEF is unclear [14]. False-positive results can be seen with diabetes, celiac disease, obesity, cirrhosis, and certain medications, including calcium channel blockers, oral contraceptives/progesterone, histamine-2 receptor antagonists, opiates, benzodiazepines, atropine, octreotide, and theophylline [12,15,16]. (See 'Diagnostic criteria' above and 'Selection of patients' below.)

Following an overnight fast, 99mTc-diisopropyl-iminodiacetic acid or 99mTc-hepatic imino-diacetic acid 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 45 minutes (30 to 60 minutes) [17]. Rapid administration of CCK (over two to three minutes) is associated with cramping, patient discomfort, and highly variable results [18]. Slower infusion rates lead to less inter- and intra-subject variability and an overall increase in mean gallbladder ejection fraction compared with rapid infusion [19-21]. 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 'Selection of patients' below.)

Following CCK infusion, the radioactivity in the region of the gallbladder is again measured and subtracted from the baseline activity (image 2).

DIFFERENTIAL DIAGNOSIS — Gallstones, gallbladder sludge, bile microcrystals, and cholesterol polyps, which are more common causes of biliary-type pain, should be ruled out by the initial ultrasound, endoscopic ultrasound, and bile microscopy. Patients with sphincter of Oddi dysfunction can have biliary pain but have elevated liver tests and/or a dilated bile duct on abdominal ultrasound. Other non-biliary causes of abdominal pain include peptic ulcer disease and functional dyspepsia, which can be diagnosed by a careful history and evaluation. (See 'Abdominal ultrasound' above and "Gallbladder polyps" and 'Initial evaluation to rule out alternative diagnoses' above.)

MANAGEMENT

Education and reassurance — Patients should be appropriately counseled that symptoms suggestive of functional gallbladder disorder can resolve spontaneously, so early intervention should be avoided [5]. However, data on the natural history of functional gallbladder disorders are limited and reported resolution rates (approximately 50 percent) in the absence of cholecystectomy are likely overestimates [22].

Cholecystectomy

Selection of patients — We suggest cholecystectomy for patients with functional gallbladder disorder and typical biliary-type pain and a low gallbladder ejection fraction (GBEF) (<40 percent) if the symptoms are severe or recur over more than three months [23]. (See "Laparoscopic cholecystectomy" and "Open cholecystectomy" and 'CCK-stimulated cholescintigraphy' above.)

Cholecystectomy should also be considered in patients with typical biliary pain and normal or even hyperkinetic ejection fraction (greater than 80 percent), as there is accumulating evidence that typical biliary pain is a better predictor of favorable response to surgery than the GBEF [24,25].

Reproduction of pain with a slow cholecystokinin (CCK) infusion has been suggested as a predictor in response to cholecystectomy [26]. However, because CCK can also increase gastrointestinal motility and lead to spasms, the specificity of this finding is questioned. (See 'CCK-stimulated cholescintigraphy' above and 'Predictors of response' below.)

Patients with atypical symptoms such as bloating, fullness, or dyspeptic symptoms are unlikely to respond to surgery even in the presence of a low GBEF and should be reassessed for alternative causes of their symptoms [27]. (See "Evaluation of the adult with abdominal pain", section on 'Diagnostic approach to chronic abdominal pain'.)

Predictors of response

●Biliary-type pain – The presence of typical biliary-type pain is the best predictor of a response to cholecystectomy [27]. The added utility of GBEF in predicting symptom outcomes after cholecystectomy is unclear [28,29]. A systematic review of nine studies that included 974 patients with suspected functional biliary pain of whom 362 patients underwent cholecystectomy [28] found no significant difference in rates of symptomatic relief after cholecystectomy in patients with a reduced or normal GBEF (94 versus 85 percent). Another 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 [29]. 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. In another meta-analysis of 1710 patients from 24 published studies, cholescintigraphy improved the predication of outcome of cholecystectomy in biliary dyskinesia by 10 percent. However, the presence of typical symptoms predicted an effective response in 70 percent of patients regardless of the GBEF, and atypical symptoms predicted a poor response [30].

●Biliary-type pain with CCK provocation – There is conflicting evidence from observational studies that the recreation of a patient's typical biliary-type pain during CCK infusion (CCK provocation) can predict a response to cholecystectomy, regardless of GBEF [26,27,31-35]. In addition, the test is limited by subjective reporting of biliary-type pain as infusion of CCK can lead to abdominal cramping, especially when infused rapidly. (See "Laparoscopic cholecystectomy" and "Open cholecystectomy" and 'CCK-stimulated cholescintigraphy' above.)

Efficacy — 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 CCK-stimulated hepatic iminodiacetic acid 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) [36]. However, the studies included in the meta-analysis had several limitations, including lack of blinding, non-randomized designs, variable lengths of follow-up, heterogeneity in methods for determining the GBEF and assessing clinical outcomes, and high rates of loss to follow-up.

Other therapies with unclear role — There are other agents that have been used to treat functional gallbladder disorder that we do not recommend due to lack of data demonstrating their efficacy. These include bile acid composition modifiers, promotility agents, and anti-inflammatory drugs [37].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cholecystitis and other gallbladder disorders".)

SUMMARY AND RECOMMENDATIONS

●Clinical manifestations – Functional gallbladder disorder is characterized by biliary pain 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. (See 'Introduction' above.)

●Diagnosis – A clinical diagnosis of functional gallbladder disorder requires the fulfillment of symptom-based diagnostic criteria for biliary pain and absence of gallstones or other structural pathology on an evaluation to exclude underlying organic disease. (See 'Diagnosis' above.)

●Evaluation to rule out alternative etiologies – Evaluation in patients with suspected functional gallbladder disorder includes a history, physical examination, and limited testing to evaluate for the presence of organic disease. In all patients, we perform the following (see 'Initial evaluation to rule out alternative diagnoses' above):

•Blood tests – We assess serum alanine aminotransferase, aspartate aminotransferase, conjugated and unconjugated bilirubin, alkaline phosphatase, amylase, and lipase. (See "Choledocholithiasis: Clinical manifestations, diagnosis, and management" and "Clinical manifestations and diagnosis of acute pancreatitis".)

•Abdominal ultrasound – An abdominal ultrasound serves to exclude gallstones, sludge, cholesterol polyps, and microcrystal disease. (See 'Abdominal ultrasound' above.)

•Upper endoscopy and endoscopic ultrasound – If the transabdominal ultrasound is negative, we perform an upper endoscopy and endoscopic ultrasound (EUS) to exclude acid peptic disease and small stones, respectively. If upper endoscopy and EUS are negative, bile is collected during the same exam and microscopy is performed to look for microlithiasis/biliary microcrystal disease. An additional evaluation may be needed in selected cases based on the clinical presentation. (See 'Upper endoscopy, EUS, and bile microscopy' above.)

●Assessment of gallbladder emptying – In patients with typical biliary pain and no evidence of gallstones or other organic causes of pain on initial evaluation, we perform cholecystokinin (CCK)-stimulated cholescintigraphy to evaluate the gallbladder ejection fraction (GBEF). A low GBEF is supportive of the diagnosis of functional gallbladder disorder but is not required to establish the diagnosis and is not specific for the diagnosis when abnormal. (See 'CCK-stimulated cholescintigraphy' above and "Functional dyspepsia in adults".)

●Management – Symptoms suggestive of functional gallbladder disorder can resolve spontaneously so early intervention should be avoided. In patients with functional gallbladder disorder with typical biliary-type pain that is recurrent (over at least three months) or severe, we suggest cholecystectomy rather than medical management (Grade 2B). (See 'Predictors of response' above and 'CCK-stimulated cholescintigraphy' above.)