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Reproduction of Postprandial Symptoms With Cholecystokinin Injection

August 3, 2007

By Cofer, Joseph B Dart, B W IV; Adams, David B; Gadacz, Thomas

Quantitative cholescintigraphy with cholecystokinin injection is commonly used to assess patients without evidence of cholelithiasis but with functional biliary pain. However, normal results may not always exclude the possibility of pathologic biliary disease. Retrospective review of prospectively collected data on eight patients with biliary colic, no evidence of cholelithiasis, a normal quantitative cholescintigraphy ejection fraction but with reproduction of their specific symptoms on cholecystokinin injection was performed. The mean ejection fraction was 66.2 per cent. All of these patients underwent cholecystectomy with complete resolution of their symptoms. Pathology was abnormal in all cases. Patients with symptoms suggestive of biliary disease with reproduction of these symptoms on cholecystokinin injection may benefit from cholecystectomy even in the absence of abnormally low ejection fraction on quantitative cholescintigraphy. POSTPRANDIAL EPIGASTRIC AND right upper quadrant pain often accompanied by nausea, vomiting, bloating, or belching is frequently secondary to biliary colic and gallbladder disease. If the presence of gallstones is detected by radiologic imaging, the clinical decision-making is straightforward, and cholecystectomy is indicated. Under these circumstances, the procedure is associated with a high rate of cure.1, 2 However, the diagnosis and treatment plan are not as clearcut when the patient does not demonstrate gallstones on imaging. At this point, if the patient’s history is strongly suggestive for biliary colic, quantitative cholescintigraphy (HIDA scan) is frequently performed. If the results demonstrate an abnormally low gallbladder ejection fraction (GBEF), the patient may be offered cholecystectomy with reported success rates of 85 per cent to 96 per cent.3-5

The purpose of this study is to report on a group of patients who were evaluated and treated by one surgeon over a 7-year period. These patients all had a normal GBEF on HIDA scanning, all had their unique postprandial symptoms reproduced by the cholecystokinin (CCK) injection during the test, and none had gallstones demonstrated by preoperative imaging.

Patients and Methods

Between September 1, 1999, and April 30, 2006, a single surgeon in an academic practice performed 448 laparoscopic cholecystectomies with or without an intraoperative cholangiogram. During that time period, data on those patients who underwent cholecystectomy based on the unique triad of biliary symptoms, a normal ultrasound, and HIDA scan but with CCK reproduction of their symptoms were collected. Their office and hospital charts were retrospectively reviewed. Standard demographic data were obtained. In addition, we collected data concerning: weight loss, duration of symptoms, abdominal ultrasound results, HIDA scan results, reaction to CCK injection, preoperative laboratory values, operation performed, and pathology reports. All patients were seen postoperatively within 2 weeks.

Results

Eight patients for review representing 1 .8 per cent of all patients undergoing cholecystectomy during the study period were identified. There were four women with a mean age of 36.5 years (range, 29-43 years) and four men with a mean age of 43 years (range, 27-54 years). Two of the eight patients had been symptomatic less than 1 month, three between 2 and 6 months, and three between 1 and 4 years. All had classic symptoms of episodic right upper quadrant and/or midepigastric postprandial pain. All had their specific symptoms reproduced by the CCK injection during HIDA scan. All eight patients had an abdominal ultrasound that showed no stones, no biliary ductal dilation, and no right upper quadrant fluid, although one did show thickening of the gallbladder wall. In addition to their abdominal ultrasound and HIDA scan, six of the eight patients had an abdominal computed tomography scan that showed no gallbladder or biliary disease except for redemonstration of gallbladder wall thickening in one. Five patients also had undergone upper endoscopy without any significant abnormal findings. All had normal preoperative liver function tests, except for one patient with Gilbert’s syndrome, one patient with a mildly elevated alkaline phosphatase and aspartate aminotransferase, and one patient with a mildly elevated alanine aminotransferase. In addition, one patient with normal liver function tests had mildly elevated amylase.

The four women had an average GBEF of 68 per cent (range, 42- 94%) and the men 64 per cent (range, 44-90%). None of the women reported significant weight loss, but three of the four men reported an average loss of 27 pounds before surgery.

Six patients underwent a laparoscopic cholecystectomy alone, whereas two had an intraoperative cholangiogram (one with elevated alkaline phosphatase and one with elevated amylase) as well. Both intraoperative cholangiograms appeared normal. All patients had resolution of their symptoms, including weight loss, after cholecystectomy. Of the 8 gallbladders removed, pathology revealed chronic cholecystitis in 3, chronic cholecystitis with cholelithiasis in 3, chronic cholecystitis with focal acute cholecystitis in 1, and cholesterolosis in 1.

Discussion

In today’s medical climate with technologic advances and ever- improving diagnostic modalities, it is not infrequent in clinical practice to encounter a patient who fully expects a surgical procedure (cholecystectomy) to completely relieve their symptoms because they have been told a “test” (HIDA scan) showed an abnormality (gallbladder dysfunction). However, unless the history and physical examination support the diagnosis of biliary colic/ disease, it is prudent to consider alternative diagnostic possibilities. Perhaps more common is the case of the symptomatic patient who is denied surgical consultation because all of the “tests” were “normal.” Typical symptoms of biliary colic, together with the presence of gallstones on an imaging study, will generally lead to a surgical consultation. So, the clinical dilemma is what to do when the history and physical examination suggest a biliary origin but the abdominal ultrasound shows no abnormalities characteristic of biliary tract disease.

In this setting, a HIDA scan is frequently performed. During this test, a CCK injection is given and a GBEF is measured. When the GBEF is low, usually less than 35 per cent, gallbladder disease is often assumed and cholecystectomy is warranted.3-8 On the other hand, there is evidence that an abnormal GBEF does not always indicate gallbladder disease.9 A prospective study of 93 patients demonstrated that although the positive predictive value of an abnormal GBEF was high, it was not much better than the clinical impression and the sensitivity and specificity was marginal.10 In a similar fashion, other single-center studies do not support the use of a low GBEF as the indication for cholecystectomy.”11, 12

In an attempt to resolve these conflicting data, a large systematic review of multiple studies assessing the predictive value of the HIDA scan was performed. Twenty-three studies were included. There were multiple methodological problems. Twenty were retrospective case series and only one was randomized. Studies varied in their outcome measures and the criteria for success. The low methodological quality of the studies precluded a meta-analysis approach to this data. The finding of the study was that a conclusion could not be reached and prospective randomized data were needed. ‘ 3 Another attempt to review this subject was a meta- analysis that included nine studies with a total of 974 patients with suspected functional biliary pain. Three hundred sixty-two of these patients underwent cholecystectomy. Ninety-four per cent of the patients with reduced GBEF had a positive outcome compared with 85 per cent of those with a normal GBEF. The study concluded that GBEF should not be used to select patients with functional biliary pain for cholecystectomy.14 Therefore, the preponderance of evidence does not support not use of GBEF as the sole indication for cholecystectomy.

Over 40 years ago, Cozzolino et al. described the “cystic duct syndrome” and proposed that reproduction of a patient’s symptoms after CCK injection (in the setting of cholecystokinin oral cholecystography) would predict good outcome after cholecystectomy.15 This maneuver of using a CCK injection to provoke the patient’s typical postprandial symptoms became known as “cholecystokinin provocation test.” One small pilot study has demonstrated that use of a CCK-I receptor blocker, loxiglumide, obtains pain relief in patients with biliary colic better than traditional anticholinergics.16 In other words, blocking the patient’s own CCK receptors during an attack decreased the pain. This implies that the pain subscribed to an attack of biliary colic is CCK mediated. Although in a larger, prospective study involving 58 patients over a 4-year period, there was no significant difference between the symptomatic outcomes after cholecystectomy between preoperative cholecystokinin provocation test-positive and – negative patients.17 So apparently, much like the degree of GBEF, there is not good evidence in the literature to support using cholecystokinin provocation test to help decide who may benefit from cholecystectomy for the diagnosis of acalculous cholecystitis. The stated purpose of our study was to present a small group of patients who had classic symptoms, all of whom had resolution of their symptoms after cholecystectomy and all of whom did not have expected results during preoperative testing. It has not been our routine practice to remove gallbladders in patients with suspected acalculous biliary disease unless 1) the history and physical was consistent, and 2) the HIDA scan was clearly abnormal. Defining an abnormal HIDA scan result in respect to ejection fraction alone is problematic with commonly referenced values reported as less than 35 per cent or less than 50 per cent. In this series, the cutoff value for abnormal was chosen to be less than 35 per cent.18 Other authors have also stressed the importance of combining a careful history and physical together with the HIDA scan results rather than simply assuming the results of a HIDA scan will predict outcome.18-20 Our data suggest that an additional subset of patients, in which CCK injection clearly reproduces specific symptoms, may actually have pathologic biliary disease and would benefit from cholecystectomy. However, the relationship between abnormal histopathologic findings and clinical disease remains speculative at best. Gallbladders removed for a clinical diagnosis of acalculous cholecystitis show chronic inflammatory changes 90 per cent of the time, but those removed incidentally as well as in autopsy series show similar changes 75 per cent to 90 per cent of the time.20 Therefore, because of the conflicting results of previously published studies, the lack of a control group in the current study, and the retrospective nature of this review, definitive recommendations cannot be made and prospective data are certainly needed. Nevertheless, we do find it intriguing that clinical impression combined with the reproducibility of specific biliary symptoms after CCK injection accurately predicted resolution of symptoms with removal of pathologically abnormal gallbladders in this small case series.

Conclusion

We believe biliary colic secondary to abnormal gallbladder pathology does occur despite “normal” findings on standard diagnostic tests. Treatment, in this situation, should be based on a thoughtful, thorough history and physical examination performed by an experienced surgeon. The absence of gallstones on imaging studies, or the “normal” GBEF on HIDA scan, should not alone be the reason to withhold cholecystectomy in the patient with classic symptoms of biliary colic, particularly if the CCK injection during HIDA scanning reproduces that patient’s unique symptoms.

REFERENCES

1. Schirmer BD. Winters KL, Edlich RF. Cholelithiasis and cholecystitis. J Long Term Eff Med Implants 2005:15:329-38.

2. Fenster LF, Lonborg R, Thirlby RC, Traverso LW. What symptoms does cholecystectomy cure? Insights from an outcomes measurement project and review of the literature. Am J Surg 1995; 169:533-8.

3. Chen PFM, Nimeri A, Pham QHT, et al. The clinical diagnosis of chronic acalculous cholecystitis. Surgery 2001;130:578-83.

4. Klieger PS, O’ Mara RE. The clinical utility of quantitative cholescintigraphy: the significance of gallbladder dysfunction. Clin Nucl Med 1998;23:278-82.

5. Nora PF, Davis RP, Fernandez MJ. Chronic acalculous gallbladder disease: a clinical enigma. World J Surg 1994;8:106-10.

6. Yap L, Wycherley AG, Morphett AD, Toouli J. Acalculous biliary pain: cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology 1991;101:786-93.

7. Canfield AJ, Hertz SP, Schriver JP, et al. Biliary dyskinesia: a study of more than 200 patients and review of the literature. J Gastrointest Surg 1998;2:443-8.

8. Krishnamurthy GT. Krishnamurthy S, Brown PH. Constancy of variability of gallbladder ejection fraction: Impact on diagnosis and therapy. J Nucl Med 2004;45:1872-77.

9. Goncalves RM, Harris JA, Rivera DE. Biliary dyskinesia: natural history and surgical results. Am Surg 1998:64:493-8.

10. Young SB, Arregui M, Singh K. HIDA scan ejection fraction does not predict sphincter of Oddi hypertension or clinical outcome in patients with suspected chronic acalculous cholecystitis. Surg Endose 2006; (Epub ahead of print).

1 1 . Westlake PJ, Hershfield NB, Kelly JR, et al. Chronic right upper quadrant pain without gallstones: does HIDA scan predict outcome after cholecystectomy? Am J Gastroenterol 1990;85:986-90.

12. Mishkind MT, Pruitt RF, Bambini DA, et al. Effectiveness of cholecystokinin- stimulated cholescintigraphy in the diagnosis and treatment of acalculous gallbladder disease. Am Surg 1997; 63:769- 74.

13. DiBaise JK, Oleynikor D. Does gallbladder ejection fraction predict outcome after cholecystectomy for suspected chronic acalculous gallbladder dysfunction? A systematic review. Am J Gastroenterol 2003;98:2605-11.

14. Delgado-Aros S. Cremonini F, Bredenoord AJ. Camilleri M. Systematic review and meta-analysis: does gall-bladder ejection fraction on cholecystokinin cholescintigraphy predict outcome after cholecystectomy in suspected functional biliary pain? Aliment Pharmacol Ther 2003;18:167-74.

15. Cozzolino H, Goldstein F, Greening R, et al. The cystic duct syndrome. JAMA 1963;185:100-4.

16. Malesci A, Pezzilli R, D’Amato M, Rovati L. CCK-I receptor blockade for treatment of biliary colic: a pilot study. Aliment Pharmacol Ther 2003;18:333-7.

17. Smythe A, Majeed AW, Fitzhenry M, Johnson AG. A requiem for the cholecystokinin provocation test? Gut 1998;43:57l^t.

18. Patel NA, Lamb JL, Hogle NJ, Fowler DL. Therapeutic efficacy of laparoscopic cholecystectomy in the treatment of biliary disease. Am J Surg. 2004;187:209-12.

19. Cunningham CC, Sehon JK, Johnson LW, Zibari GB. Outcomes of surgical therapy for biliary dyskinesia. J LA State Med Soc. 2003;155:189-91.

20. Lillemoe KD. Chronic acalculous cholecystitis: are we diagnosing a disease or a myth? Radiology 1997;204:13-4.

JOSEPH B. COFER, M.D., B.W. DART IV, M.D.

From the Department of Surgery, University of Tennessee College of Medicine-Chattanooga, Chattanooga, Tennessee

Presented during the Plenary Session at the Annual Scientific Meeting and Postgraduate Course Program, Southeastern Surgical Congress, Savannah, GA, February 10-13, 2007.

Address correspondence and reprint requests to: Joseph B. Cofer, M.D., University of Tennessee College of Medicine-Chattanooga, Department of Surgery, 979 East Third Street, Suite B401, Chattanooga, TN 37403. E-mail: coferjb@erlanger.org.

DISCUSSION

DR. DAVID B. ADAMS (Charleston, SC; Opening Discussion): Chronic acalculous cholecystitis, also known as functional gallbladder disease, acalculous biliary tract disease, and biliary dyskinesia, is a timely topic that deserves discussion. Laparoscopic cholecystectomy for chronic acalculous cholecystitis has skyrocketed with the advent of the laparoscopic revolution. Thirteen per cent of the laparoscopic cholecystectomies at my institution are undertaken for acalculous cholecystitis and 23 per cent is the figure in another reported series. Dr. Cofer reported 1.7 per cent of laparoscopic cholecystectomies successfully performed over a 6-year period in patients who had a normal gallbladder ultrasound and normal biliary scintigraphy. This experience highlights the potential fallacy of biliary scintigraphy in a diagnosis of chronic acalculous cholecystitis. He has properly described the importance to the clinical history, which in this report is the symptom elicited by intravenous CCK injection.

In our reported experience with CCK biliary scintigraphy, so- called positive and negative scans were not predictive either of success or failure with likelihood positive and negative ratios around 1 . 1 agree with the way you said using nuclear scintigraphy for the diagnosis of chronic acalculous cholecystitis is the equivalent of saying, “spin the wheel, Vanna.”"Wheel of Fortune’s” Vanna White, as most of you know, is from South Carolina. We avoid spinning the nuclear medicine “Wheel of Fortune” with our patients with biliary pain and will proceed directly to laparoscopic cholecystectomy without scintigraphy when the history and assessment are appropriate. In the preoperative discussion, this is what I tell my patients and is what I would like to emphasize today.

Twenty per cent of Americans have gallstones; only 20 percent of those with gallstones have symptoms. Most gallstones do not cause biliary-type pain. Gallstones may cause pain when they obstruct the cystic duct, however. Most biliary pain is caused by gallbladder dysfunction. Stones may develop after the dysfunction starts if you wait long enough. Biliary dyskinesia does not lead to acute cholecystitis and the need for emergency cholecystectomy. The laparoscopic conversion rate is zero for this disorder. The major complication rate nevertheless remains at 0. 1 per cent. The symptom cure rate for biliary pain is 78 per cent. If pain is not better after operation or endoscopic retrograde cholangiopancreatography, then sphincter of Oddi manometry can be undertaken. If sphincter of Oddi manometry is abnormal, then endoscopic sphincterotomy will cure the pain most of the time. If the pain is not biliary pain, endoscopic sphincterotomy will not help. Laparoscopic cholecystectomy is done before sphincter of Oddi manometry and endoscopic sphincterotomy because laparoscopic cholecystectomy has a lower complication rate than endoscopic retrograde cholangiopancreatography with sphincter of Oddi manometry. Those are my biases with this disease.

In your ongoing follow up of these eight patients, have the results seen at 2 weeks persisted? Second, with your current experience, do you think it is possible to identify patients with symptomatic acalculous biliary tract disease who would benefit from laparoscopic cholecystectomy based on the history alone without the additional data you obtained with CCK injection? Lastly, what is your laparoscopic cholecystectomy success rate in patients with acalculous biliary tract disease and abnormal biliary scintigraphy? This manuscript lacks the rigors, as Dr. Cofer mentioned, of the usual evidence-based report but is a careful clinical assessment that reflects the humanity of the good surgeon and reminds me what Ben Franklin expressed in writing, “So convenient a thing it is to be a reasonable creature, since it enables one to find or make a reason for everything one has a mind to do.”

DR. THOMAS GADACZ (Augusta, GA): Did you examine the bile for cholesterol crystals? I was wondering whether these patients identified at an early stage would benefit from a trial on Urso (deoxycolate), which is a good choloretic bile salt. This might be a good preliminary test to see if there is any relief from their symptoms as opposed to doing a cholecystectomy.

DR. JOSEPH B. COFER (Chattanooga, TN; Closing Discussion): I have not made an effort to examine these patients years later by phone survey to see if they have any symptoms. Some are still my patients and have come to me for other things over the years. To the best of my knowledge, none of them have had any persistent symptoms.

I have planned surgery without a HIDA scan in the absence of gallstones. Frequently, these patients already have these tests before they come to me.

Dr. Gadacz, as for bile crystals, three of these patients had unrecognized stones, and I typically open the gallbladder in the operating room. I do not think many of these patients would want a trial of bile salts to see if their symptoms go away. Most of these people were sent to me after they had seen many doctors for some years and really wanted something done. I have not examined the bile for crystals.

Copyright Southeastern Surgical Congress Jul 2007

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