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Optimum utilization of cholecystokinin cholescintigraphy (CCK-HIDA) in clinical practice: an evidence based review.

Laparoscopic cholecystectomy

remains one of the most commonly

performed operations in the United

States. Of the cholecystectomies

performed, approximately 30% are carried

out for a diagnosis of gallbladder

dyskinesia, for which diagnosis is based

on a reduced gallbladder ejection fraction

as determined by a sincalide

(cholecystokinin) stimulated hepatobiliary

iminodiacetic scan (CCK-HIDA). Despite

the widespread acceptance of this

practice standardization of the test

methodology and high quality data

indicating efficacy of cholecystectomy in

the treatment of this condition are lacking.

This manuscript reviews this problem in

detail based on the current available

literature.

Introduction

Cholecystokinin-cholescintigraphy (CCK-HIDA) is commonly performed to evaluate patients with upper abdominal pain thought to be biliary in origin and in whom the gallbladder is found to be normal on ultrasound. Cholecystectomy is commonly performed based on the finding of an abnormally low gallbladder ejection fraction. (1) The testing methods and results of surgery for biliary dyskinesia are controversial and poorly understood by many clinicians. This review discusses the controversies surrounding the testing methods, the determination of normal vs. abnormal values, and the data both supporting and questioning its use in current practice.

Background

For years, surgeons, gastroenterologists and primary care physicians have encountered patients with complaints consistent with biliary disease, but with negative ultrasound imaging of the gallbladder, thus creating a diagnostic dilemma.

In 1991 a randomized, prospective study was published by Yap et al. (2) in which a population of patients with suspected pain of biliary origin (and a negative gallbladder ultrasound) underwent CCKHIDA scan with calculation of the gallbladder ejection fraction. Those with an abnormal ejection fraction (<40%) comprised the primary study group, and were randomized to either cholecystectomy or no cholecystectomy (observation) groups. Patients who underwent cholecystectomy did dramatically better than those who were merely observed. The remainder of the patients--those with pain but a with a normal ejection fraction were treated at the discretion of their doctors. Those with a normal ejection fraction who had surgery did no better than those who were observed. The Yap study concluded was that a low gallbladder ejection fraction was predictive of success in patients undergoing cholecystectomy for acalculous biliary pain. Based on these data, clinicians began offering cholecystectomy to patients who met these criteria. (2)

A Closer Look at the Yap Study

The Yap study, although interesting and widely quoted, has had a number of criticisms. First, the study population of patients with low gallbladder ejection fraction (GBEF) was only 21 patients! (11 surgery, 10 observation) Of the 11 undergoing surgery, 10 experienced total relief and one experienced improvement. Of the 10 in the observation group, all remained symptomatic, and two of these crossed over to the surgery arm and subsequently did well. (2) Amazingly, this remains the only randomized prospective trial to date examining the role of surgery in treating this condition. It was harshly criticized in a 2008 Cochrane review for not only being severely underpowered in terms of sample size, but also at significant risk of bias. (3)

Other data on the efficacy of CCK-HIDA in predicting response to cholecystectomy have been published with conflicting results, with success rates ranging from no benefit to a 96.6% cure rate. (4) A recent systematic review by DiBaise et al. (5) found that the calculation of the gallbladder ejection fraction (GBEF) was useful in selecting patients for surgery in 19 of 23 papers studied, including that of Yap et al. However, the investigators noted that the studies were small, nonrandomized, retrospective, uncontrolled, and with varying durations of follow up, with varying symptoms used to define biliary pain, and with varying definitions of successful outcome. These flaws, and the heterogeneity of the data, make it difficult, if not impossible, to draw any evidence based conclusions from it. (5)

Reasons Limiting the Usefulness of CCK-HIDA

To understand the shortcomings of these various studies, and the current knowledge gaps in this area of clinical practice, one must first understand the controversies surrounding the performance of the CCK-HIDA scan itself. A key aspect of the CCK-HIDA scan is the manner in which normal vs. abnormal gallbladder ejection fraction results are determined, and how this differs from other diagnostic tests. With the majority of diagnostic tests, an abnormal value is predictive of pathology - for example, the finding of gallstones on ultrasound, a spiculated density on mammography, or an infiltrate on chest X-ray. CCK-HIDA is distinctly different however, in that the normal vs. abnormal values for GBEF are calculated from values obtained from normal subjects, with the cutoff of normal vs. abnormal typically designated at three standard deviations from the mean. (2,6) In other words, the values are calculated from what is "normal" in the general population and "abnormal" values, by definition, are therefore not necessarily predictive of a disease state. They simply are values that fall outside the normal distribution. For this reason, it is expected that some normal volunteers will have an abnormal GBEF. Conversely, some patients with functional biliary pain may have GBEF values within the normal range.

Additionally, much controversy exists in the testing methodology. CCK-HIDA, despite widespread use in clinical practice, suffers from a lack of standardization of test methodology in several important areas. These include dose of sincalide (CCK) administered, duration of administration, and time at which GBEF is calculated. A review of the published studies on the use of CCK-HIDA revealed CCK doses from 0.005mcg/kg to 0.03 mcg/ kg, infusion durations ranging from 2-3 minutes all the way up to 45 minutes, and normal vs. abnormal cutoff values ranging from 35%-65%. In some published studies, the exact nature of the testing protocol was not even described. (7)

Zeissman et al. examined this issue in a multicenter trial designed to determine the most reliable, reproducible, and least variable protocol. They conducted studies on normal subjects with a variety of infusion and imaging protocols and found their results to be the most consistent and reproducible with a dose of 0.02mcg/kg CCK, continuously infused over 60 minutes, and with the GBEF calculated at 60 minutes. The threshold for normal vs. abnormal in their study was 38%.6 This study was only recently published however, and testing protocols continue to vary from center to center.

Finally, the test is often conducted under conditions which may adversely affect the accuracy of the results. The Society of Nuclear Medicine and other thought leaders in the nuclear medicine field have specifically stated, for example, that CCK-HIDA should be performed solely on an outpatient basis, and not while the patient is acutely ill, so that confounding factors including the effects of medications may be avoided. It is further recommended that opiates be withheld for a full four half-lives of the drug prior to testing. A number of other drugs, including benzodiazepines, atropine, nifedipine, indomethacin, octreotide, theophylline, phentolamine, and progesterone are also capable of affecting the test results and should also be avoided for several hours prior to testing. Failure to adhere to these recommendations may result in lower values for GBEF than would be obtained under optimal test conditions in the same patient. (8)

Proper Patient Selection

Patient selection may also be an issue that has affected the reliability of CCK-HIDA in predicting symptom relief after cholecystectomy. Current expert opinion based on the available data favors cholecystectomy for patients with biliary symptoms and an abnormal GBEF, and discourages cholecystectomy in cases involving atypical symptoms. (1,9) The definition of what constitutes the most appropriate and valid description of biliary symptoms is a matter of debate and has been a source of controversy in previously published reviews on this subject. (5) Symptoms however remain crucial in selecting which patients should undergo diagnostic biliary testing, including CCK-HIDA. It only seems logical that removal of the gallbladder will be of greatest benefit to those patients suffering from gallbladder pathology. Furthermore, in the review by DiBaise and Oleynikov, the authors commented that a standardized and reliable set of diagnostic criteria for functional biliary pain was important in selecting patients for further biliary testing (CCK-HIDA). (5) The results of their pooled analysis revealed that outcomes were better in selected patients--i.e., those with biliary symptoms and an abnormal GBEF. Outcomes were not improved in patients with biliary symptoms and a normal GBEF when compared with observational controls. (5)

These data, although once again limited by the retrospective nature of the study, the heterogeneity of the pooled data, and the high risk of bias, suggest the need for reliable diagnostic criteria in the selection of patients for CCK-HIDA, since it is the combination or typical symptoms and an abnormal GBEF that provide the best chance of success with operation.

Other misconceptions involving patient selection for surgery based on the results of CCK-HIDA are worth mentioning. One such misconception is the assumption that the degree of lowering of GBEF is predictive of success. (In other words, a GBEF of 3% is more likely have a favorable response to cholecystectomy than a patient with the same symptoms but a GBEF of 24%). This has not proven to be the case in the data published to date. (10) Another misconception involves the idea that the reproduction of patient symptoms with CCK injection is another predictor of success with cholecystectomy. This assumption has also proven to be false. CCK is known to stimulate other organs besides the gallbladder, including the small intestine and stomach, which may produce unpleasant pain and cramping. When administered intravenously, especially in a 2-3 minute infusion protocol, unpleasant symptoms are not uncommon and have no predictive value with respect to relief of biliary pain with cholecystectomy. (11)

The Rome III criteria for functional gallbladder disorder (Table I), is perhaps the best known standardized symptom complex for the diagnosis of functional gallbladder disorder and the subsequent selection of patients to undergo CCK-HIDA scanning for suspected biliary dyskinesia. (12) The ordering of CCKHIDA studies in patients with atypical symptoms not suggestive of functional biliary disorder should be discouraged, as some of these patients may indeed have an abnormal GBEF in the absence of disease. Failure to grasp this concept may result in inappropriate referrals for surgery, thereby subjecting the patient to unnecessary risk and a higher likelihood of no benefit from cholecystectomy.

Summary

Based on review of the current literature on this topic, it seems appropriate to conclude:

* The use of CCK-HIDA scan (and GBEF) to select which patients with pain of biliary origin should undergo cholecystectomy is an acceptable practice under current Society of Gastrointestinal and Laparoendocopic Surgeons (SAGES) clinical guidelines.

* The use of the CCK-HIDA should be restricted to those patients meeting criteria for functional biliary pain/ functional gallbladder disorder according to established criteria, such as those proposed by the Rome III committee. The use of CCK-HIDA in the investigation of atypical symptoms should be avoided.

* No data exist to suggest that symptom reproduction with CCK injection or degree of GBEF abnormality is predictive of relief of symptoms by cholecystectomy, and these criteria should not be used to select patients for surgery.

* Clinicians should adhere to the recommendations of the Society of Nuclear Medicine with respect to the conduct of the CCK-HIDA scan, and to which medications should be held prior to testing, so that the chances of false positive scans is minimized.

* Further study is needed to define the optimal protocol for dosing schedule, CCK infusion time, and cutoff value for normal vs. abnormal values. The recent work of Zeissman et al. proposing that this should be 0.02mcg/ kg infused over 60 minutes, with the cutoff value for normal being 38% is a laudable attempt to standardize the practice, but the results will need to be replicated in subsequent studies.

* More randomized, prospective, well-controlled trials are needed investigating the role of CCKHIDA scan in the diagnosis of acalculous bilary pain/functional gallbladder disorder, and in patient selection for the surgical treatment of this condition.

References

(1.) SAGES guidelines committee. Society of American Gastrointestinal and Endoscopic Surgeons guidelines for the clinical application of laparoscopic biliary tract surgery. Published January 2010. http://www.sages.org/publication/id/06/ (accessed 8/13/10).

(2.) Yap I, Wycherly A, Morphett A, Toouli J. Acalculous biliary pain: cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology 1991; 101(3):786-93.

(3.) Gurusamy KS, Junnarkar S, Farouk M, Davidson BR. Cholecystectomy for suspected gallbladder dyskinesia, Cochrane Database of Sysyematic Reviews 2009; Issue 1, Art no. CD007086.

(4.) Hofeldt M, Richmond B, Huffman K, Nestor J, Maxwell D. Laparoscopic cholecystectomy for treatment of biliary dyskinesia is safe and effective in the pediatric population. Am Surgeon 2008; 74:1069-72.

(5.) DiBaise JK, Oleynikov D. Does gallbladder ejection fraction predict outcome after cholecystectomy for suspected chronic acalculous gallbladder dysfunction? A systematic review. Am J Gastroenterol 2003; 98:2605-2611.

(6.) Ziessman HA, Tulchinsky M, Lavely WC, et al. Sincalide-stimulated cholescintigraphy: a multicenter investigation to determine optimal infusion methodology and gallbladder ejection fraction normal values. J Nucl Med 2010; 51:277 281.

(7.) Rastogi A, Slivka A, Moser AJ, et al. Controversies concerning pathophysiology and management of acalculous biliary-type abdominal pain. Dig Dis Sci 2005; 50:1391-1401.

(8.) Tulchinsky M, Ciak B, Debelke D, et al. SNM practice guidelines for hepatobilary scintigraphy 4.0. Journal of Nuclear Med Technology 2010; 38(4):210-18.

(9.) Vassiliou M, Laycock W. Biliary dyskinesia. Surg Clin N Am 2008; 88:1253-72.

(10.) Ozden, N, DiBaise, JK. Gallbladder ejection fraction and symptom outcome in patients with acalculous biliary-like pain. Dig Dis Sci 2003; 48:890-897.

(11.) Smythe A, Majeed AW, Fitzhenry M, et al. A requiem for the cholecystokinin provocation test? Gut 1998; 43:571-574.

(12.) Behar J, Corazzari E, Guelrud M, Hohan W, Sherman S, Toouli J. Functional gallbladder and sphincter of Oddi disorders. Gastroenterology 2006; 130:1498-509.

Bryan K. Richmond, MD, MBA, FACS

Associate Professor of Surgery

West Virginia University/Charleston Division
Table I. The Rome III Criteria for Functional Gallbladder and
Sphincer of Oddi Disorders (12)

I. Functional Gallbladder and Sphincer of Oddi Disorders:

Must include episodes of pain located in the epigastrium and right
upper quadrant and all of the following:

1. Epsisodes lasing 30 minutes or longer

2. Recurrent symptoms occurring at different intervals

3. The pain builds up to a steady level.

4. The pain is severe enough to interrupt the patient's daily
activities or lead to an emergency room visit

5. The pain is not relieved by bowel movements

6. The pain is not relieved by postural change

7. The pain is not relieved by antacids

8. Exclusion of other structural diseases that would explain the
symptoms

Supportive criteria:

The pain may present with one or more of the following:

1. Associated with nausea and vomiting

2. Radiates to the back and/or right infrascapular area

3. Awakens patient from sleep in the middle of the night.

II. Functional Gallbladder Disorder

Must include all of the following:

1. Criteria for functional gallbladder and sphincter of Oddi
disorder

2. Gallbladder is present

3. Normal liver enzymes, conjugated bilirubin, and amylase/lipase
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Title Annotation:Scientific Article
Author:Richmond, Bryan K.
Publication:West Virginia Medical Journal
Article Type:Report
Geographic Code:1USA
Date:Mar 1, 2012
Words:2492
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