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Right Upper Quadrant Pain and a Normal Abdominal Ultrasound
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6:1198 –1201
EDUCATION PRACTICE Right Upper Quadrant Pain and a Normal Abdominal Ultrasound FURQAAN AHMED and EVAN L. FOGEL Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana
Clinical Scenario A 30-year-old woman is referred for evaluation of a 1-year history of intermittent, debilitating, postprandial right upper quadrant pain associated with nausea and occasional vomiting. The pain can last from 30 minutes to 2 hours, often radiates to the upper back between the shoulder blades, and is not associated with bowel movements or exercise. The patient denies a history of weight loss, fever, chills, change in urine or stool color, or jaundice. She denies significant alcohol use. Trials of antacids, proton pump inhibitors, and antispasmodics have not been helpful. At times the pain has been severe enough to interrupt her daily activities. The patient recently presented to her local emergency department during an episode of pain. Blood work drawn in the emergency department included alanine aminotransferase 23 U/L (normal, 0 – 45 U/L), aspartate aminotransferase 29 U/L (normal, 15– 41 U/L), alkaline phosphatase 86 U/L (normal, 25–125 U/L), bilirubin 0.6 mg/dL (normal, 0 –1 mg/dL), amylase 101 U/L (normal, 25–161 U/L), and lipase 162 U/L (normal, 40 –240 U/L). The patient reports that liver chemistries and amylase and lipase levels have been persistently normal during previous episodes of abdominal pain. A right upper quadrant ultrasound reveals a normalappearing gallbladder without gallbladder wall thickening or gallstones. The intrahepatic and extrahepatic bile ducts are not dilated. The liver and limited views of the pancreas are also unremarkable. The patient underwent an esophagogastroduodenoscopy (EGD) 1 month ago that was normal. What is the most likely cause for this patient’s symptoms? What is the next step in the diagnostic evaluation of this patient?
the detection of common bile duct stones, small stones and microlithiasis might be missed. Endoscopic ultrasound and microscopic bile examination for microlithiasis might be useful in a subset of these patients. The pathophysiology of acalculous gallbladder pain is not well-understood. Theories that have been proposed include those that implicate gallbladder outlet obstruction, those that point to a primary disorder of gallbladder motility, and those that implicate visceral hypersensitivity. Lack of coordination between gallbladder contraction and contractions of the sphincter of Oddi or relative cystic duct narrowing might cause functional gallbladder obstruction. Abnormal gallbladder motility might occur because of entrapment of supersaturated cholesterol crystals in the gallbladder wall, impaired response to cholecystokinin (CCK), or intrinsic defects in the gallbladder musculature. Visceral hypersensitivity might play a role in acalculous biliary pain (biliary dyskinesia) analogous to that in other functional disorders of the gastrointestinal tract. The most prominent symptom of biliary dyskinesia is right upper quadrant pain. The characteristics of this pain have been defined in the Rome III diagnostic criteria for functional gallbladder disorders (Table 1). Characteristic biliary pain is intermittent, often radiates to the right shoulder or back, is frequently associated with nausea and vomiting, and might be postprandial. Consensus criteria outlined in Rome III define this pain as not being associated with posture, exercise, or bowel movements. Jaundice and fever are usually not present. Physical examination is usually unremarkable except for mild right upper quadrant tenderness. Other Rome III requisite criteria for the diagnosis of acalculous gallbladder disease include an intact gallbladder and normal liver chemistries, amylase, and lipase.
The Problem The right upper quadrant pain in this patient is suggestive of biliary origin. However, this pain syndrome accompanied by a normal gallbladder ultrasound and normal liver function tests suggests subtle acalculous gallbladder disease. When such patients are encountered, other causes for right upper quadrant pain need to be considered and reasonably excluded. These include peptic ulcer disease, choledocholithiasis and microlithiasis, pancreatobiliary neoplasia, irritable bowel syndrome, and musculoskeletal pain. Type III sphincter of Oddi dysfunction (SOD) is also in the differential diagnosis, but because of the risks of endoscopic retrograde cholangiopancreatography (ERCP), gallbladder evaluation is usually undertaken first. Peptic ulcer disease can be diagnosed with EGD. Although ultrasound and magnetic resonance cholangiopancreatography (MRCP) have relatively high sensitivity rates for
Management Strategies and Supporting Evidence In the past, several tests were used to assess gallbladder contractility. These included the CCK pain provocation test to determine reproducibility of symptoms with gallbladder contraction, CCK cholecystography, or right upper quadrant ultraAbbreviations used in this paper: CCK, cholecystokinin; EGD, esophagogastroduodenoscopy; ERCP, endoscopic retrograde cholangiopancreatography; HIDA, hepato-iminodiacetic acid; MRCP, magnetic resonance cholangiopancreatography; SOD, sphincter of Oddi dysfunction. © 2008 by the AGA Institute 1542-3565/08/$34.00 doi:10.1016/j.cgh.2008.06.020
November 2008
RIGHT UPPER QUADRANT PAIN AND A NORMAL ABDOMINAL ULTRASOUND
Table 1. Diagnostic Criteria for Functional Gallbladder Disorders Episodes of epigastric and/or right upper quadrant pain in a patient with an intact gallbladder and normal liver chemistries and amylase/lipase that meet all the following criteria: 1. Episodes of pain lasting 30 minutes or longer 2. Recurrent symptoms occurring at varying intervals (not daily) 3. Gradual buildup of pain intensity to a steady level 4. The pain is severe enough to interrupt the patient’s activities and/or lead to an emergency department visit. 5. The pain is not relieved by bowel movements. 6. The pain is not relieved by postural changes. 7. The pain is not relieved by antacids. 8. Structural diseases that could explain the patient’s symptoms have been excluded. The pain might present with 1 or more of the following supportive criteria: 1. Pain associated with nausea and vomiting 2. Pain radiates to the back and/or right subscapular region. 3. Pain awakens patient from sleep in the middle of the night. Adapted from Behar J, Corazziari E, Guelrud M, et al. Functional gallbladder and sphincter of Oddi disorders. Gastroenterology 2006; 130:1498 –1509.
sonography after CCK administration or a meal to measure gallbladder volume. However, these methods are no longer widely used because of issues with reproducibility, operator dependency, and low sensitivity and specificity. Noninvasive assessment of gallbladder emptying by using 99mtechnetium-labeled hepato-iminodiacetic acid (99mTcHIDA) cholescintigraphy, or HIDA scan, was first described in 1981 and is currently the test used most often for the diagnosis of subtle acalculous gallbladder disease. The iminodiacetic acid is avidly taken up by the liver, excreted with bile, and then concentrated in the gallbladder. The gallbladder ejection fraction is measured after the administration of CCK; the degree of gallbladder emptying is dependent on both the dose and rate of CCK administration. A low ejection fraction is indicative of gallbladder dysfunction. Some patients report reproduction of their right upper quadrant pain during this test. Although it has been suggested that this reproduction of symptoms might predict a good response to cholecystectomy, this point remains controversial. When gallbladder dysfunction is suggested by HIDA scan, a cholecystectomy is often recommended. In fact, suspicion of acalculous gallbladder disease is primarily responsible for the significant increase in the frequency of cholecystectomy during the past 2 decades. Several studies have looked at outcomes after cholecystectomy is performed for this indication, but most are limited by retrospective study design and small patient numbers. However, a sentinel study by Yap and colleagues did suggest a benefit of surgery. This group prospectively randomized patients with acalculous biliary symptoms and an HIDA scan documenting a gallbladder ejection fraction ⬍40% to cholecystectomy (n ⫽ 11) or no surgery (n ⫽ 10). Mean follow-up was 34 months. Of the patients who underwent a cholecystectomy, 10 had complete symptom relief, and 1 had partial relief. In contrast, all of the patients in the nonoperative group remained symptomatic; 2 underwent surgery during the follow-up period. Ponsky and colleagues performed a meta-analysis of surgical therapy for acalculous gallbladder disease, evaluating 274 patients
1199
culled from 5 studies. In patients with gallbladder dysfunction documented by HIDA scan, symptomatic improvement occurred in 98% of patients who underwent a cholecystectomy compared with 32% in those managed nonoperatively. Total symptom relief occurred in 74% of patients who underwent surgery but in only 8% of those who did not.
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.
1200
AHMED AND FOGEL
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 11
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 longterm 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
Figure 1. Suggested algorithm for evaluation of patients with right upper quadrant pain and a normal abdominal ultrasound.
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 rea-
November 2008
RIGHT UPPER QUADRANT PAIN AND A NORMAL ABDOMINAL ULTRASOUND
sonably 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). Suggested Reading 1. Balon HR, Fink-Bennett DM, Brill DR, et al. Procedure guideline for hepatobiliary scintigraphy. J Nucl Med 1997;38:1654 –1657.
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2. Behar J, Corazziari E, Guelrud M, et al. Functional gallbladder and sphincter of Oddi disorders. Gastroenterology 2006;130:1498 – 1509. 3. Krishnamurthy GT, Bobba VR, Kingston E. Radionuclide ejection function: a technique for quantitative analysis of motor function of the human gallbladder. Gastroenterology 1981;80:482– 490. 4. Ponsky TA, DeSagun R, Brody F. Surgical therapy for biliary dyskinesia: a meta-analysis and review of the literature. J Laparoendosc Adv Surg Tech 2005;15:439 – 442. 5. Society for Surgery of the Alimentary Tract. Treatment of gallstone and gallbladder disease. Available at: www.ssat.com/cgi-bin/ chole7.cgi. 6. Yap L, Wycherley G, Morphett AD, et al. Acalculous biliary pain: cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology 1991;101:786 –793. 7. Sherman S, Fogel EL, Watkins JL, et al. Sphincter of Oddi dysfunction. In: Ginsberg G, Kochman M, Norton I, et al, eds. Clinical gastrointestinal endoscopy. London: Elsevier Health Sciences, 2005.
Address requests for reprints to: Evan L. Fogel, MD, Division of Gastroenterology & Hepatology, Department of Medicine, Indiana University Hospital, 550 N University Boulevard, #4100, Indianapolis, IN 46202. e-mail: [email protected]; fax: 317-278-0164. The authors disclose no financial conflicts of interest.
EDUCATION PRACTICE Right Upper Quadrant Pain and a Normal Abdominal Ultrasound FURQAAN AHMED and EVAN L. FOGEL Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana
Clinical Scenario A 30-year-old woman is referred for evaluation of a 1-year history of intermittent, debilitating, postprandial right upper quadrant pain associated with nausea and occasional vomiting. The pain can last from 30 minutes to 2 hours, often radiates to the upper back between the shoulder blades, and is not associated with bowel movements or exercise. The patient denies a history of weight loss, fever, chills, change in urine or stool color, or jaundice. She denies significant alcohol use. Trials of antacids, proton pump inhibitors, and antispasmodics have not been helpful. At times the pain has been severe enough to interrupt her daily activities. The patient recently presented to her local emergency department during an episode of pain. Blood work drawn in the emergency department included alanine aminotransferase 23 U/L (normal, 0 – 45 U/L), aspartate aminotransferase 29 U/L (normal, 15– 41 U/L), alkaline phosphatase 86 U/L (normal, 25–125 U/L), bilirubin 0.6 mg/dL (normal, 0 –1 mg/dL), amylase 101 U/L (normal, 25–161 U/L), and lipase 162 U/L (normal, 40 –240 U/L). The patient reports that liver chemistries and amylase and lipase levels have been persistently normal during previous episodes of abdominal pain. A right upper quadrant ultrasound reveals a normalappearing gallbladder without gallbladder wall thickening or gallstones. The intrahepatic and extrahepatic bile ducts are not dilated. The liver and limited views of the pancreas are also unremarkable. The patient underwent an esophagogastroduodenoscopy (EGD) 1 month ago that was normal. What is the most likely cause for this patient’s symptoms? What is the next step in the diagnostic evaluation of this patient?
the detection of common bile duct stones, small stones and microlithiasis might be missed. Endoscopic ultrasound and microscopic bile examination for microlithiasis might be useful in a subset of these patients. The pathophysiology of acalculous gallbladder pain is not well-understood. Theories that have been proposed include those that implicate gallbladder outlet obstruction, those that point to a primary disorder of gallbladder motility, and those that implicate visceral hypersensitivity. Lack of coordination between gallbladder contraction and contractions of the sphincter of Oddi or relative cystic duct narrowing might cause functional gallbladder obstruction. Abnormal gallbladder motility might occur because of entrapment of supersaturated cholesterol crystals in the gallbladder wall, impaired response to cholecystokinin (CCK), or intrinsic defects in the gallbladder musculature. Visceral hypersensitivity might play a role in acalculous biliary pain (biliary dyskinesia) analogous to that in other functional disorders of the gastrointestinal tract. The most prominent symptom of biliary dyskinesia is right upper quadrant pain. The characteristics of this pain have been defined in the Rome III diagnostic criteria for functional gallbladder disorders (Table 1). Characteristic biliary pain is intermittent, often radiates to the right shoulder or back, is frequently associated with nausea and vomiting, and might be postprandial. Consensus criteria outlined in Rome III define this pain as not being associated with posture, exercise, or bowel movements. Jaundice and fever are usually not present. Physical examination is usually unremarkable except for mild right upper quadrant tenderness. Other Rome III requisite criteria for the diagnosis of acalculous gallbladder disease include an intact gallbladder and normal liver chemistries, amylase, and lipase.
The Problem The right upper quadrant pain in this patient is suggestive of biliary origin. However, this pain syndrome accompanied by a normal gallbladder ultrasound and normal liver function tests suggests subtle acalculous gallbladder disease. When such patients are encountered, other causes for right upper quadrant pain need to be considered and reasonably excluded. These include peptic ulcer disease, choledocholithiasis and microlithiasis, pancreatobiliary neoplasia, irritable bowel syndrome, and musculoskeletal pain. Type III sphincter of Oddi dysfunction (SOD) is also in the differential diagnosis, but because of the risks of endoscopic retrograde cholangiopancreatography (ERCP), gallbladder evaluation is usually undertaken first. Peptic ulcer disease can be diagnosed with EGD. Although ultrasound and magnetic resonance cholangiopancreatography (MRCP) have relatively high sensitivity rates for
Management Strategies and Supporting Evidence In the past, several tests were used to assess gallbladder contractility. These included the CCK pain provocation test to determine reproducibility of symptoms with gallbladder contraction, CCK cholecystography, or right upper quadrant ultraAbbreviations used in this paper: CCK, cholecystokinin; EGD, esophagogastroduodenoscopy; ERCP, endoscopic retrograde cholangiopancreatography; HIDA, hepato-iminodiacetic acid; MRCP, magnetic resonance cholangiopancreatography; SOD, sphincter of Oddi dysfunction. © 2008 by the AGA Institute 1542-3565/08/$34.00 doi:10.1016/j.cgh.2008.06.020
November 2008
RIGHT UPPER QUADRANT PAIN AND A NORMAL ABDOMINAL ULTRASOUND
Table 1. Diagnostic Criteria for Functional Gallbladder Disorders Episodes of epigastric and/or right upper quadrant pain in a patient with an intact gallbladder and normal liver chemistries and amylase/lipase that meet all the following criteria: 1. Episodes of pain lasting 30 minutes or longer 2. Recurrent symptoms occurring at varying intervals (not daily) 3. Gradual buildup of pain intensity to a steady level 4. The pain is severe enough to interrupt the patient’s activities and/or lead to an emergency department visit. 5. The pain is not relieved by bowel movements. 6. The pain is not relieved by postural changes. 7. The pain is not relieved by antacids. 8. Structural diseases that could explain the patient’s symptoms have been excluded. The pain might present with 1 or more of the following supportive criteria: 1. Pain associated with nausea and vomiting 2. Pain radiates to the back and/or right subscapular region. 3. Pain awakens patient from sleep in the middle of the night. Adapted from Behar J, Corazziari E, Guelrud M, et al. Functional gallbladder and sphincter of Oddi disorders. Gastroenterology 2006; 130:1498 –1509.
sonography after CCK administration or a meal to measure gallbladder volume. However, these methods are no longer widely used because of issues with reproducibility, operator dependency, and low sensitivity and specificity. Noninvasive assessment of gallbladder emptying by using 99mtechnetium-labeled hepato-iminodiacetic acid (99mTcHIDA) cholescintigraphy, or HIDA scan, was first described in 1981 and is currently the test used most often for the diagnosis of subtle acalculous gallbladder disease. The iminodiacetic acid is avidly taken up by the liver, excreted with bile, and then concentrated in the gallbladder. The gallbladder ejection fraction is measured after the administration of CCK; the degree of gallbladder emptying is dependent on both the dose and rate of CCK administration. A low ejection fraction is indicative of gallbladder dysfunction. Some patients report reproduction of their right upper quadrant pain during this test. Although it has been suggested that this reproduction of symptoms might predict a good response to cholecystectomy, this point remains controversial. When gallbladder dysfunction is suggested by HIDA scan, a cholecystectomy is often recommended. In fact, suspicion of acalculous gallbladder disease is primarily responsible for the significant increase in the frequency of cholecystectomy during the past 2 decades. Several studies have looked at outcomes after cholecystectomy is performed for this indication, but most are limited by retrospective study design and small patient numbers. However, a sentinel study by Yap and colleagues did suggest a benefit of surgery. This group prospectively randomized patients with acalculous biliary symptoms and an HIDA scan documenting a gallbladder ejection fraction ⬍40% to cholecystectomy (n ⫽ 11) or no surgery (n ⫽ 10). Mean follow-up was 34 months. Of the patients who underwent a cholecystectomy, 10 had complete symptom relief, and 1 had partial relief. In contrast, all of the patients in the nonoperative group remained symptomatic; 2 underwent surgery during the follow-up period. Ponsky and colleagues performed a meta-analysis of surgical therapy for acalculous gallbladder disease, evaluating 274 patients
1199
culled from 5 studies. In patients with gallbladder dysfunction documented by HIDA scan, symptomatic improvement occurred in 98% of patients who underwent a cholecystectomy compared with 32% in those managed nonoperatively. Total symptom relief occurred in 74% of patients who underwent surgery but in only 8% of those who did not.
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.
1200
AHMED AND FOGEL
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 11
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 longterm 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
Figure 1. Suggested algorithm for evaluation of patients with right upper quadrant pain and a normal abdominal ultrasound.
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 rea-
November 2008
RIGHT UPPER QUADRANT PAIN AND A NORMAL ABDOMINAL ULTRASOUND
sonably 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). Suggested Reading 1. Balon HR, Fink-Bennett DM, Brill DR, et al. Procedure guideline for hepatobiliary scintigraphy. J Nucl Med 1997;38:1654 –1657.
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2. Behar J, Corazziari E, Guelrud M, et al. Functional gallbladder and sphincter of Oddi disorders. Gastroenterology 2006;130:1498 – 1509. 3. Krishnamurthy GT, Bobba VR, Kingston E. Radionuclide ejection function: a technique for quantitative analysis of motor function of the human gallbladder. Gastroenterology 1981;80:482– 490. 4. Ponsky TA, DeSagun R, Brody F. Surgical therapy for biliary dyskinesia: a meta-analysis and review of the literature. J Laparoendosc Adv Surg Tech 2005;15:439 – 442. 5. Society for Surgery of the Alimentary Tract. Treatment of gallstone and gallbladder disease. Available at: www.ssat.com/cgi-bin/ chole7.cgi. 6. Yap L, Wycherley G, Morphett AD, et al. Acalculous biliary pain: cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology 1991;101:786 –793. 7. Sherman S, Fogel EL, Watkins JL, et al. Sphincter of Oddi dysfunction. In: Ginsberg G, Kochman M, Norton I, et al, eds. Clinical gastrointestinal endoscopy. London: Elsevier Health Sciences, 2005.
Address requests for reprints to: Evan L. Fogel, MD, Division of Gastroenterology & Hepatology, Department of Medicine, Indiana University Hospital, 550 N University Boulevard, #4100, Indianapolis, IN 46202. e-mail: [email protected]; fax: 317-278-0164. The authors disclose no financial conflicts of interest.