Areas of Uncertainty

Cholescintigraphy

Despite its frequent use for the diagnosis of subtle gallbladder disease, there are several unresolved questions regarding cholescintigraphy. Measurements of gallbladder ejection fraction are influenced by the dose, rate, and duration of CCK infusion, none of which are currently standardized. Although the original description of this test by Krishnamurthy and colleagues used a 3-minute CCK infusion, it appears that 30- to 60-minute infusions most closely resemble physiologic conditions. Nonphysiologic doses and rates of CCK infusion might result in falsely low estimates of gallbladder ejection fraction and might lead to results that are not reproducible. Published studies on cholescintigraphy have used varying methods of CCK administration. The Society of Nuclear Medicine has published guidelines for performing hepatobiliary scintigraphy but did not recommend a particular dose and duration of CCK. The product insert for Kinevac (sincalide), a synthetic form of CCK, describes 3 different methods of administration to stimulate gallbladder contraction. Furthermore, a uniform threshold for abnormal gallbladder ejection fraction cannot be standardized without uniform administration of CCK. Most published data have defined gallbladder dysfunction as an ejection fraction less than 35%–40%. It has also been suggested that a hypercontractile gallbladder (ejection fraction > 85%) might result in similar biliary-type pain.

The finding of impaired gallbladder emptying on an HIDA scan is not 100% specific for gallbladder dysfunction. Several other conditions might also cause impaired emptying, including obesity, diabetes, pregnancy, cirrhosis, celiac disease, and medications (calcium channel blockers, opioids, anticholinergics, and sex hormones). Because patients with significant pain might be on narcotic analgesics or antispasmodics, gallbladder emptying as demonstrated by cholescintigraphy might be falsely depressed.

Outcomes After Cholecystectomy

Although there are data to support surgery for acalculous gallbladder disease, several questions remain unanswered. Not all patients with gallbladder dysfunction (as suggested by a low ejection fraction) who have symptom improvement after cholecystectomy have complete relief. The cause for only partial relief after removal of a dysfunctional gallbladder is unclear but might occur because there is another primary cause for symptoms, or that the diseased gallbladder was only one element of a multifactorial pain syndrome. Furthermore, there are anecdotal data of patients with normal gallbladder function on HIDA scan who have symptom improvement after cholecystectomy, and some studies have shown similar responses to surgery in patients both with and without abnormal gallbladder emptying. Unfortunately, there are no reliable predictors of which patients with biliary-type pain and a documented low gallbladder ejection fraction will respond to cholecystectomy. Finally, the degree of diminished gallbladder contractility based on HIDA scan has not been shown to correlate with outcome after cholecystectomy.

The long-term outcome of acalculous biliary pain after cholecystectomy is perhaps least studied. The mean follow-up period of the studies included in the meta-analysis by Ponsky and colleagues ranged from 9–30 months. An assessment of long-term response to surgery, therefore, cannot be made. In a study of pediatric patients with low gallbladder ejection fractions, patients who underwent surgery had a high rate of symptomatic response to surgery at 1-month follow-up. However, at 2-year follow-up, the proportion of patients with symptomatic improvement was similar among those who underwent surgery and those who did not. The natural history of gallbladder dysfunction is not known. However, one study found that if patients with gallbladder dysfunction documented by low gallbladder ejection fraction on HIDA scan undergo repeat HIDA scan months to years later, the gallbladder ejection fraction remains low.

Sphincter of Oddi Dysfunction

SOD dysfunction is another potential cause of upper abdominal pain. This classically presents as recurrent or continued upper quadrant pain after cholecystectomy. There are several unanswered questions regarding SOD and gallbladder dysfunction: (1) does SOD occur in patients with an intact gallbladder, (2) is there an association between SOD and gallbladder dysfunction, and (3) what is the role of SOD and subtle gallbladder dysfunction in the evaluation and management of patients with right upper quadrant pain and a normal ultrasound?

There are limited data on the frequency of SOD in patients with an intact gallbladder. However, SOD has been documented in up to 10% of patients with symptomatic gallstones and 50% of patients with biliary-type pain and a normal gallbladder ultrasound. It is unknown whether there is an association between sphincter of Oddi hypertension and gallbladder dysfunction. Although some investigators have found a similar frequency of SOD in patients with and without gallbladder dysfunction, other investigators have reported similar gallbladder ejection fractions in patients with and without documented SOD. In a prospective study conducted to study the relationship between SOD and gallbladder dysfunction, 81 patients with biliary-type pain and an intact, sonographically normal gallbladder underwent both sphincter of Oddi manometry and HIDA cholescintigraphy. Of 41 patients with a normal HIDA scan, 57% had SOD; of 40 patients with an abnormal HIDA scan, 50% had SOD. Data from this study suggest that both SOD and gallbladder dysfunction are common in this group of patients and appear to occur independently of one another.

Patients with disabling right upper quadrant pain, a normal abdominal ultrasound, and normal liver tests, amylase, and lipase might have gallbladder dysfunction or SOD. In evaluating a patient without objective evidence of pancreatobiliary pathology and whose gallbladder is intact, the question arises as to whether conservative medical therapy or additional evaluation/intervention should be pursued. The diagnosis of gallbladder dysfunction is usually made on the basis of results of the noninvasive HIDA scan. Therefore, in a patient with an intact gallbladder, the diagnosis of subtle acalculous gallbladder disease is usually considered before SOD, given that the latter requires ERCP with manometry for diagnosis and is associated with more risk. Even in tertiary referral centers, performance of ERCP/SOD manometry is associated with a 10%–15% risk of complications leading to hospitalization (infection, bleeding, perforation, pancreatitis). With recent advances in the performance/safety of ERCP (eg, pancreatic stent placement), serious complications are much less commonly seen but do continue to occur. Limited outcome data in type III SOD patients from retrospective series have suggested a 40%–70% pain relief rate with sphincterotomy. Prospective data, however, are lacking and are eagerly awaited. If an HIDA scan reveals a normal gallbladder ejection fraction, the decision whether to proceed with ERCP or empiric cholecystectomy requires a thorough discussion of risks versus benefits with the patient and should be made on a case-by-case basis.

Published Guidelines

The Rome III conference presented diagnostic criteria for functional gallbladder disorders but did not provide guidelines for the management of these patients. Treatment guidelines for gallstone and gallbladder disease published by the Society for Surgery of the Alimentary Tract in 2006 recommend consideration of surgery in patients with recurrent biliary-type pain and documented biliary dysfunction (defined as a gallbladder ejection fraction less than 30% on cholescintigraphy). The Society also suggested that evaluation by a gastroenterologist, including endoscopic assessment, might be useful in the management of some of these patients.

Recommendations

The patient described in this case scenario with right upper quadrant pain and a normal ultrasound has been reasonably evaluated for nonbiliary causes of pain. An EGD is normal. Liver chemistries and pancreatic enzymes have been persistently normal, even during episodes of severe pain. A computed tomography scan could be considered to further evaluate the biliary tract for structural pathology, with consideration given to performing endoscopic ultrasound or MRCP for more detailed evaluation if suspicion is high. The patient has tried smooth muscle relaxants without benefit. Her symptoms have significantly impaired her quality of life and have required emergency department visits. We recommend determination of gallbladder ejection fraction by cholescintigraphy. If decreased gallbladder ejection fraction is documented, a cholecystectomy would be warranted, despite the areas of uncertainty noted earlier. Although cholecystectomy would be expected to offer symptomatic relief, it might also be considered a diagnostic test in this patient. If the ejection fraction is normal or symptoms persist after cholecystectomy, an ERCP with manometry might be considered in this patient with debilitating symptoms. (Figure 1).

Figure 1.  (click image to zoom) Suggested algorithm for evaluation of patients with right upper quadrant pain and a normal abdominal ultrasound.

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