Clinical presentation

A critical question that has plagued clinicians for many years is what exactly constitutes biliary-like abdominal pain? Biliary-like abdominal pain originally was described as a pain in the right upper quadrant that was colicky in nature and associated with fatty food intake and various nonspecific gastrointestinal (GI) symptoms. In contrast, the definition recently endorsed by the Rome committee on functional biliary and pancreatic disorders describes biliary-like pain as episodic, severe, steady pain located in the epigastrium or right upper quadrant that lasts at least 30 minutes and is severe enough to interrupt daily activities or require consultation with a physician ( Box 1 ). The pain may be accompanied by nausea and vomiting, radiate to the back or infrascapular region, or awaken the patient from sleep. In general, an irregular periodicity between episodes is characteristic, and the relationship to eating is unreliable. Importantly, pain lasting more than 6 hours is unlikely to be related to the gallbladder when gallstones are not present, and serologic liver and pancreas tests are normal unless due to a complication of gallstone disease (eg, acute cholecystitis, pancreatitis). Despite this clarification of the clinical criteria, there continues to be confusion and significant overlap with other functional GI disorders requiring further validation of these criteria.

Pathogenesis

Presumably, the pain associated with functional gallbladder disorder may occur due to increased gallbladder pressure caused by either structural or functional outflow obstruction. Similar to other functional GI disorders, the pathophysiology of functional gallbladder disorder remains poorly understood and may, in fact, represent a constellation of mechanisms. Multiple theories of pathogenesis have been proposed including cholesterolosis, microlithiasis, biliary sludge, chronic cholecystitis, gallbladder dysmotility, narrowed cystic duct, cystic duct spasm, sphincter of Oddi dysfunction, and visceral hypersensitivity. Two studies, one by Velanovich and one by Brugge, reported a significant association between crystal formation in the bile or in the walls of the gallbladder in patients with functional biliary pain who had undergone cholecystectomy, suggesting that bile saturation or gallbladder dysmotility may lead to crystal growth and eventually gallstones or chronic inflammation. Presumably, pain may occur at any point during the process. Abnormal gallbladder histology, however, has not been a universal finding in patients who experience symptom relief following cholecystectomy for presumed functional biliary pain, with studies reporting changes of chronic cholecystitis ranging from 44% to 100%. Furthermore, it remains unclear whether the histologic changes in the gallbladder are a cause or an effect of poor gallbladder contractility.

Impaired gallbladder emptying resulting from hypokinesia of the gallbladder or dyskinesia due to partial obstruction distal to the gallbladder, either structural or functional, also might be responsible for functional gallbladder disorder. Interestingly, given the not uncommon occurrence of abnormalities in gastric emptying and colon transit in these patients, it has been suggested that functional gallbladder disorder may reflect a panenteric motility disorder. The role of dysfunction at the level of the sphincter of Oddi in patients with presumed functional gallbladder disorder remains unclear. To clarify this relationship, Ruffolo and colleagues conducted a prospective study of patients with biliary-type pain and normal-appearing gallbladder. Patients were tested extensively with quantitative cholescintigraphy, sphincter of Oddi manometry, and endoscopic retrograde cholangiopancreatography (ERCP). Approximately 50% of patients were found to have a normal gallbladder ejection fraction (GBEF), and within this group, 57% were found to have sphincter of Oddi dysfunction. Of the patients with low GBEF, 50% also were found to have sphincter of Oddi dysfunction. These findings are supported by results from another study that also failed to find a correlation between sphincter of Oddi pressure and GBEF. Thus, it appears abnormalities in GBEF and sphincter of Oddi pressure occur independent of one another.

Pathogenesis

Presumably, the pain associated with functional gallbladder disorder may occur due to increased gallbladder pressure caused by either structural or functional outflow obstruction. Similar to other functional GI disorders, the pathophysiology of functional gallbladder disorder remains poorly understood and may, in fact, represent a constellation of mechanisms. Multiple theories of pathogenesis have been proposed including cholesterolosis, microlithiasis, biliary sludge, chronic cholecystitis, gallbladder dysmotility, narrowed cystic duct, cystic duct spasm, sphincter of Oddi dysfunction, and visceral hypersensitivity. Two studies, one by Velanovich and one by Brugge, reported a significant association between crystal formation in the bile or in the walls of the gallbladder in patients with functional biliary pain who had undergone cholecystectomy, suggesting that bile saturation or gallbladder dysmotility may lead to crystal growth and eventually gallstones or chronic inflammation. Presumably, pain may occur at any point during the process. Abnormal gallbladder histology, however, has not been a universal finding in patients who experience symptom relief following cholecystectomy for presumed functional biliary pain, with studies reporting changes of chronic cholecystitis ranging from 44% to 100%. Furthermore, it remains unclear whether the histologic changes in the gallbladder are a cause or an effect of poor gallbladder contractility.

Impaired gallbladder emptying resulting from hypokinesia of the gallbladder or dyskinesia due to partial obstruction distal to the gallbladder, either structural or functional, also might be responsible for functional gallbladder disorder. Interestingly, given the not uncommon occurrence of abnormalities in gastric emptying and colon transit in these patients, it has been suggested that functional gallbladder disorder may reflect a panenteric motility disorder. The role of dysfunction at the level of the sphincter of Oddi in patients with presumed functional gallbladder disorder remains unclear. To clarify this relationship, Ruffolo and colleagues conducted a prospective study of patients with biliary-type pain and normal-appearing gallbladder. Patients were tested extensively with quantitative cholescintigraphy, sphincter of Oddi manometry, and endoscopic retrograde cholangiopancreatography (ERCP). Approximately 50% of patients were found to have a normal gallbladder ejection fraction (GBEF), and within this group, 57% were found to have sphincter of Oddi dysfunction. Of the patients with low GBEF, 50% also were found to have sphincter of Oddi dysfunction. These findings are supported by results from another study that also failed to find a correlation between sphincter of Oddi pressure and GBEF. Thus, it appears abnormalities in GBEF and sphincter of Oddi pressure occur independent of one another.

Natural history

The natural history of functional gallbladder disorder is poorly understood. Information can be gleaned from a recent study by Krishnamurthy and colleagues They found that a low GBEF based on cholecystokinin-cholescintigraphy (CCK-CS) remains low on repeat testing months to years later. The severity of GBEF reduction increased with time. In those with a normal GBEF, about 30% became abnormally low after a mean duration of about 53 months between studies. How these changes correlate with symptoms over time remains poorly defined.

Additional information on the natural history of this disorder can be learned from an assessment of the outcome of the nonsurgical arms of studies conducted on patients with suspected functional gallbladder disorder. Yap and colleagues randomized 21 patients with abnormal GBEF to cholecystectomy versus no surgery and followed the patients for up to 54 months. Of the 10 patients in the no surgery group, all continued to report symptoms of functional gallbladder disorder. A more recent study reported similar findings, with 50% of patients with abnormal GBEF reporting resolution in symptoms up to 4 years after cholecystectomy, compared with only 16% of those with abnormal GBEF who elected not to pursue cholecystectomy ( P = .039). In contrast, a retrospective study by Ozden and DiBaise found that 50% of patients with an abnormal GBEF who did not undergo cholecystectomy reported clinical remission of symptoms after up to 3 years of follow-up, similar to the 64% of patients with a normal GBEF who reported resolution of their symptoms. Another retrospective study gathered information from 58 patients treated at two community hospitals, 42 of whom had an abnormal GBEF. Of those 42 patients, 12 of 15 who did not undergo cholecystectomy reported lessening or resolution of symptoms. Finally, a study by Gonclaves and colleagues reported 75% of patients with suspected functional gallbladder disorder who did not have cholecystectomy had persistent symptoms, and only 25% had resolution of symptoms without any treatment. Clearly, these results need to be interpreted with caution given the retrospective nature of most of these studies, the variable length of follow-up and criteria of symptom outcome, and the small number of patients evaluated.

Diagnostic tests

In the setting of biliary-like abdominal pain and a normal gallbladder on transcutaneous ultrasound, the diagnosis of functional gallbladder disorder requires a careful evaluation to exclude other causes of the symptoms, and, at a minimum, serologic testing of liver and pancreatic enzymes and upper endoscopy. Several tests have been developed in an attempt to more objectively implicate the gallbladder as the source of the symptoms. The technique of analyzing aspirated bile from the biliary system or duodenum to assess for microlithiasis has not been widely accepted due to technical issues with the procedure and poor specificity. The use of CCK-provocation of abdominal pain when deciding whether to proceed with cholecystectomy is discouraged. Smythe and colleagues evaluated 58 patients with functional biliary pain who underwent CCK provocation test and gallbladder volumetry before cholecystectomy and did not find a significant difference in symptom outcome following cholecystectomy between CCK provocation positive and negative patients. Furthermore, CCK administration, particularly when infused over a few minutes, is known to stimulate not only the gallbladder but also the duodenum and colon. Because small stones (<5 mm) may be missed with traditional transabdominal ultrasonography, three studies have prospectively evaluated patients with biliary-type pain and a normal transabdominal ultrasound using endoscopic ultrasound of the gallbladder, finding a significant number of patients with cholecystolithiasis. In one of these studies, 76% of the patients offered cholecystectomy were pain-free at their 1-year follow-up. Despite these encouraging reports, this technique is not yet widely available, and further studies are necessary to determine its clinical utility, cost-effectiveness, and overall place in the evaluation of these patients.

Functional assessment of gallbladder emptying before and after gallbladder stimulation using either a fatty meal or CCK is currently the most common test used to evaluate patients with suspected functional gallbladder disorder. Oral cholecystography, both with and without CCK stimulation, has demonstrated variable results regarding symptom outcome and is considered insufficiently reliable as a measure of gallbladder function. Presently, CCK-CS with measurement of the GBEF is the most commonly used test to aid in the diagnosis of functional gallbladder disorder. Although controversial, the use of CCK-CS has been supported by the Rome committee, which has recommended that, in the presence of biliary-like pain, an absence of gallstones on abdominal ultrasound, and normal liver and pancreatic enzymes, CCK-CS should be the next diagnostic step ( Fig. 1 ).

Suggested algorithm for the diagnosis and treatment of suspected functional biliary pain in patients with a gallbladder. ∗using slow CCK infusion for at least 30 minutes. CCK-CS, cholecystokinin cholescintigraphy; GBEF, gallbladder ejection fraction.

Reproduced from DiBaise JK. Evaluation and management of functional biliary pain in patients with an intact gallbladder. Expert Rev Gastroenterol Hepatol 2009;3(3):305–13; with permission.

Caveats relating to the use of cholecystokinin–cholescintigraphy

CCK-CS involves the intravenous administration of ^99m technetium-labeled hepato-iminodiacetic acid, which is taken up by the liver and excreted into the biliary system, where it accumulates in the gallbladder. A GBEF then can be measured reliably after stimulating gallbladder emptying, most commonly with CCK. A low GBEF has been suggested to be indicative of gallbladder dysfunction and supportive of a diagnosis of functional gallbladder disorder; however, its use is not without controversy. This is reflected in clinical practice by the not uncommon scenario of patients with suspected functional biliary pain and a reduced GBEF reporting no or incomplete relief of symptoms or recurrence of symptoms following cholecystectomy.

It is important to recognize that the finding of a low GBEF is not specific for functional gallbladder disorder and may occur in asymptomatic, healthy individuals, in patients with various medical conditions including diabetes, celiac disease, or irritable bowel syndrome, and as a result of a number of medications such as opioid analgesics, calcium channel blockers, oral contraceptive agents, histamine-2 receptor antagonists, and benzodiazepines. It also must be recognized that the gallbladder may not be responsible for a decreased GBEF as, occasionally, outflow obstruction from abnormalities of the cystic duct or sphincter of Oddi may be responsible. Therefore, this test should be considered only when there is a high index of suspicion of a gallbladder origin of the symptoms and other diagnoses have been eliminated. Furthermore, when considering whether to perform CCK-CS, it is preferable for it to be performed as an outpatient procedure on a patient who is not having pain at the time given the potential of confounding effects of acute illness in the hospitalized patient who may be receiving multiple medications.

The clinician should be familiar with how the test is performed and interpreted at his or her institution. At present, there is no consensus on the dose, rate, and duration of CCK infusion used in CCK-CS. Many CCK-CS studies are conducted using a rapid infusion of CCK over 2 to 3 minutes, a methodology that has been shown to yield highly variable results. In contrast, the slow infusion of CCK over 30 to 60 minutes results in an overall increase in mean GBEF compared with its rapid infusion and less inter- and intrasubject variability. Regarding CCK-CS interpretation, there remains no consensus on the definition of an abnormal GBEF, although most clinicians consider a value of less than 35% as abnormal. A multicenter trial is in progress that is attempting to determine the best methodology and establish normal values in a large healthy population.