Chronic Biliary-Type Pain in the Absence of Gallstones: The Value of Cholecystokinin Cholescintigraphy

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1 509 Review Chronic Biliary-Type Pain in the Absence of Gallstones: The Value of Cholecystokinin Cholescintigraphy R. Kloiber,1 C. P. Molnar,1 and E. A. Shaffer Radiologic criteria for the diagnosis of gallbladder disease largely rest on the detection of calculi. Surgeons are reluctant to do a cholecystectomy in patients with symptoms of gallbladder disease if the results of sonography or cholecystography are normal. Consequently these patients are often left with no satisfactory treatment. Such patients may have chronic acalculous cholecystitis, partial obstruction of the cystic duct, or gallbladder dyskinesia. Increasing evidence indicates that at least some of these patients have decreased gallbladder emptying in response to a stimulus such as a test meal or cholecystokinin. Impaired emptying shown by cholecystokinin cholescintigraphy may be useful for predicting which patients with typical biliary-type pain but no evidence of calculi will be cured by cholecystectomy. Most patients with biliary-type pain are initially examined with sonography, a procedure that has a sensitivity approaching 98% for detecting calculi [1]. However, sonographic findings are normal in a subset of patients with typical biliary-type pain. Detection of abnormal gallbladder emptying may be an indication of which of these patients will be cured by cholecystectomy even though they had no stones. In this review, we describe the technique used to perform cholecystokininstimulated cholescintigraphy, the limitations of the procedure, and the results of various clinical studies. Cholescintigraphy Radiooharmaceuticals Analogues of Tc-iminodiacetic acid (9 Tc-IDA) are the most frequently used radiopharmaceuticals for hepatobiliary Article imaging. After IV injection, these organic anions are taken up by hepatocytes in afashion similar to bilirubin and rose bengal. The anions are secreted into bile canaliculi without conjugation. The radiopharmaceutical is uniformly mixed with bile and transverses the biliary system; part fills the gallbladder, and the remainder exits into the duodenum. No significant intestinal reabsorption or enterohepatic recycling occurs [2]. The ideal agent has a high extraction efficiency (>80%) by the liver, rapid transit, and high concentration in bile. Gallbladder Filling In healthy fasting patients, the gallbladder is usually visualized within 15 mm after a bolus injection of the radiopharmaceutical and almost always within 60 mm. Time-activity curves generated from the filling phase of the gallbladder vary and may show either a progressively rising curve, a stepwise rising curve, or spontaneous decreases caused by contraction that is probably associated with the migratory myoelectric complex. This spontaneous contractile wave originates in the lower esophagus or gastric antrum and sweeps down the small intestine during the interdigestive period about every 120 mm in humans. After a bolus injection, the concentration of mtc-lda within bile peaks and then declines slowly. The rate of rise, peak, and rate of decline vary with different 99mTclDA analogues. Externally detected changes in radioactivity within the gallbladder are consequently not proportional to the volume of Received October 21, 1991; accepted after revision March 23, Department of Radiology, Foothills Hospital and University of Calgary, th St. NW., Calgary, Alberta, Canada T2N 2T9. Address reprint requests to R. Kloiber. 2Department of Medicine, Foothills Hospital and University of Calgary, Calgary, Alberta, Canada, T2N 2T9. AJR 159: , September X/92/ American Roentgen Ray Society

2 510 KLOIBER ET AL. AJR:159, September 1992 bile entering the gallbladder. The concentration of bile and dilution of the radiopharmaceutical by existing unlabeled bile within the gallbladder are additional variables that negate using cholescintigraphy to directly measure gallbladder volume. The best use of the filling phase is to confirm patency of the cystic duct. Gallbladder Emptying Although externally detected radioactivity is independent of absolute volume as described, radioactivity is proportional to relative volume so long as no additional bile enters the gallbladder. It is also independent of the gallbladder s shape and geometry. Time-activity curves reflecting relative volume can be generated from a region of interest over the gallbladder on digitized dynamic images from the emptying phase. Background correction is done by subtracting radioactivity detected in a region of interest adjacent to the gallbladder region from the gallbladder time-activity curve after normalizing the area of the regions. Decreasing radioactivity of the Tc-lDA due to decay also must be corrected for. The most commonly used single measurement that reflects the degree of emptying is the ejection fraction, which represents the percentage of initial volume or activity evacuated with contraction of the gallbladder. Although measurements at only two discrete time points are required for the calculation, generation of a time-activity curve is desirable to ensure that maximum and minimum volumes were selected. Algonthms to calculate the ejection fraction are available on most dedicated nuclear medicine computer systems and are done according to the formula: EF = [(A - Bga) (B Bgb)]/ (A - B9a), where EF = ejection fraction, A = initial gallbladder radioactivity from a region of interest on a digitized image, Bg0 = background normalized to the initial gallbladder region of interest (A), B = decay-corrected gallbladder radioactivity after stimulated contraction, and B9b = decay-corrected background radioactivity normalized to the postcontraction gallbladder region of interest (B). This method assumes complete mixing of the radiopharmaceutical with bile; the ejection fraction can be overestimated if sludge or abundant stones are present. mtcida does not adhere to either calculi or the wall of the gallbladder [3]. This method has been validated in vitro and is simple, accurate, reproducible, and operator-independent in clinical use [4]. Other factors such as emptying rates can be calculated from the time-activity curves but have not been studied extensively. Stimulus for Contraction For clinical purposes, gallbladder contraction can be initiated by either a test meal or infusion of cholecystokinin or its synthetic active octapeptide (sincalide [Kinevac], Squibb Canada Inc., Montreal, Canada). The variety of protocols used by investigators complicates comparisons of different studies. It can be argued that the test meal is more physiologic and therefore is the preferred approach when information is sought about the function of the gallbladder in the overall digestive process. The meal, however, introduces additional variables. The composition of the meal will affect the endogenous release of cholecystokinin from the duodenal mucosa directly and indirectly because meals of different composition have different rates of emptying from the stomach. Furthermore, impaired gastric emptying will blunt or delay the response, as will pancreatic insufficiency [5] or mucosal diseases, such as sprue [6]. Administration of cholecystokinin provides control of the dose, resulting in a more reproducible measure of gallbladder contractility. Cholecystokinin has been administered by either bolus injection or slow IV infusion. With slow infusion (more than 5 mm as a minimum), gallbladder response is dosedependent above a threshold and reaches a plateau above which higher doses do not further enhance emptying [7, 8]. Rapid bolus injection results in submaximal emptying and can produce abdominal discomfort [9, 1 0]. The optimized slowinfusion rate of cholecystokinin octapeptide is pg/kg per hour. Maximal gallbladder emptying and maximal ejection fraction are reached around 1 hr after the infusion is begun. With the slow-infusion technique that we use, subjects rarely experience pain, whether they are control subjects, patients with stones who are being examined for medical dissolution therapy, or patients with noncalculous biliary-type pain, even if their symptoms subsequently decreased after cholecystectomy. Pain reproduction is therefore a poor indicator of disease and should not be used as a criterion. Effects of Medications and Nonbillary Diseases Because of the complex neural and humoral control of gallbladder contractility, many medications and physiologic states can alter the results. Morphine in particular and opiates in general cause impaired gallbladder emptying because they induce spasm of the sphincter of Oddi [11]. Endogenous opiates secreted after major upper abdominal surgery may contribute to impaired contraction [1 2]. Truncal vagotomy results in increased gallbladder volume and decreased contractility [1 3, 14]. Atropine inhibits [1 5] and cholinergic stimulation enhances gallbladder emptying [1 6]. Calcium channel blockers reduce contractility, presumably by interfering with the calcium-mediated contraction of smooth muscle [17]; emptying is enhanced by hypercalcemia [1 8]. In animals, stimulation of histamine2 receptors also can be inhibitory [1 9]. Considering the wide variety of medications with similar actions, great care must be exercised to ensure accurate results. Systemic diseases also may have an effect on an intrinsically normal gallbladder. Decreased contractility and increased gallbladder volume have been described in diabetic patients who have advanced neuropathy [20, 21], in patients with sickle cell hemoglobinopathy [22], and in large persons [23]. A generalized smooth muscle abnormality with impaired cholecystokinin response has been shown in patients with irritable bowel syndrome [24]. Gallbladder contraction in response to a test meal appears to be unaffected by the age of the patient. In older patients, contraction may be maintained

3 AJR:159, September 1992 CHOLECYSTOKININ CHOLESCINTIGRAPHY FOR BILIARY PAIN 511 by an exaggerated endogenous cholecystokinin release in response to food [25], and therefore contraction in response to a standardized cholecystokinin infusion may be subnormal. Progesterone has been shown to impair gallbladder emptying [26], but differences in gallbladder ejection fraction due to the sex of the patient, phases of the menstrual cycle, and use of oral contraceptives have been inconsistent. Many of these factors have not been accurately defined but may account in part for the lack of consistency shown in clinical studies of gallbladder disease. The Significance of Reduced Contraction Some patients with histologically proved acalculous cholecystitis have impaired contraction [27]. These patients may be at an earlier stage of a process that leads eventually to calculous disease. The mechanism of reduced emptying could be related to an inherent impairment of contractility that contributes to stone formation [28, 29]. A direct effect of lithogenic bile on contractility has been shown even before stone formation in animal models [30] and patients [31]. Cholesterol crystals in bile are considered a precursor of stone formation, and symptomatic patients with crystals have been shown to have a lower ejection fraction than those without crystals [32]. The release of endogenous cholecystokinin also may be impaired after a meal [33]. In late stages, defective emptying could be caused by fibrosis and thickening of the gallbladder wall associated with chronic inflammation. Impaired contraction does not appear to be related to the presence of stones themselves [34]. In one series, only 24% of 67 patients with proved chronic calculous cholecystitis had impaired gallbladder contraction [35]. It is reasonable to assume that a significant number of patients with acalculous cholecystitis will have normal emptying. Impaired gallbladder contraction also may exist in the absence of symptoms: in one study of chronic calculous gallbladder disease in which cholecystectomy was not performed, only 18% of patients had symptoms during 15 years of follow-up [36]. Cystic duct syndrome with partial noncalculous obstruction of the cystic duct [37] and gallbladder dyskinesia also have been proposed to explain biliary pain. The standard selected for confirming an abnormality is therefore problematic. Histologic evidence of chronic cholecystitis will be absent if the pain is caused by dyskinesia alone. A small cystic duct, adhesions, or kinking may be difficult to confirm, even at surgery. Pain relief after surgery may be a more appropriate indicator but is not reliable unless the clinical trial is well controlled with a long follow-up because of the placebo effect of surgery. It is therefore not surprising that different investigators have had different results and different opinions on the value of gallbladder motility studies. Results of Clinical Studies The degree of gallbladder evacuation measured by cholecystography after a bolus injection of cholecystokinin showed wide variation (ejection fraction of 10-90%) in a series of control subjects in the study of Nathan et al. [38]. In a trial by Dunn et al. [39] in which three radiologists had no knowledge of which subjects had symptoms, between 10% and 36% of control subjects were considered to have abnormal cholecystographic findings of decreased contraction and asymmetric spasm after bolus injection of cholecystokinin. This was not statistically different from findings in patients who had biliary colic or dyspepsia. High interobserver variability of up to 28% also was found. These results did not help predict histologic abnormalities or relief of symptoms after cholecystectomy. The failure of cholecystokinin-stimulated oral cholecystography can be attributed to the nonphysiologic method and subjective criteria for interpretation. Gallbladder emptying as measured by scintigraphy with cholecystokinin stimulation is quantitative. Nevertheless, nonphysiologic, rapid infusions of cholecystokinin also will cause incomplete contraction of the gallbladder even in control subjects, leading some authors to conclude that the degree of contraction cannot be used to indicate presence of chronic acalculous cholecystitis [40]. Abnormal contraction cannot be used to accurately predict histologic evidence of chronic inflammation [40, 41], as would be expected if pain also could result from a motility disorder. Others [42-44], who also used a rapid injection of cholecystokinin (less than 5 mm), have taken a more positive view of the value of the procedure on the basis of a high rate of clinical response ( %) in patients with reduced emptying who had surgery. Indeed, all series [41-44] showed favorable response rates ( %) comparable to those in patients who had surgery for calculi [45, 46]. All the studies were retrospective and primarily involved patients with abnormal emptying, yet by no means did all the patients with abnormal emptying have surgery. It is also likely that of the patients with abnormal emptying, those with more typical or more severe symptoms had cholecystectomy. Surgeons generally do not operate on the basis of symptoms alone, yet in one series [42], five of five patients who had normal evacuation also had pain relief with subsequent cholecystectomy. With the lack of a histologic basis, the vagaries of clinical assessment, the selection bias, and the small number and proportion of patients who have surgery, it is impossible to calculate meaningful sensitivity and specificity figures. For future investigation, standardization of the method of cholecystokinin cholecystography is essential. Patients should be eating normally up to a minimum of 2 hr to no more than 24 hr before the study to ensure that gallbladder filling will occur. Ideally, all medications should be discontinued. Infusion of cholecystokinin at a physiologic dose rate is preferable to a test meal unless gastric emptying is measured simultaneously. Patients with advanced diabetes, liver disease, pancreatitis, irritable bowel syndrome, or previous upper gastrointestinal surgery should not have the procedure. Although it is unlikely that a prospective study randomizing patients to have surgery regardless of their ejection fractions will be done, a recent study by Yap et al. [47] sheds additional light on the question. The gallbladder ejection fraction was calculated in 103 patients 1 hr after the beginning of a 45-mm

4 512 KLOIBER ET AL. AJR:159, September 1992 cholecystokmnin-octapeptide infusion at pg/kg per hour. An ejection fraction of less than 40% (3 SD less than the mean ejection fraction of the control group) was arbitrarily defined as abnormal. Twenty-one patients with a reduced ejection fraction were randomized to have surgery, and of the 11 operated on, 10 became asymptomatic and one had partial relief of symptoms. The patients who did not have surgery remained symptomatic. Of the 82 patients with normal ejection fractions, 50 were asymptomatic on follow-up and 10 were symptomatic without specific treatment for biliary disease. Fourteen others had cholecystectomy, and eight of these became asymptomatic. Eight patients were not available for follow-up. All patients in the group with a low ejection fraction had evidence of chronic cholecystitis, muscle hypertrophy, or a narrowed cystic duct. Similar findings were seen in six of the normally contracting gallbladders that were removed. These results suggest that an abnormal ejection fraction is a good predictor of a favorable response to surgery, but eight patients with normal ejection fractions also benefited from cholecystectomy. If it is assumed that all 21 patients with low ejection fractions would have improved with surgery and it is known that at least eight with normal ejection fractions responded favorably to surgery, the maximum sensitivity of low ejection fractions as an indicator of the desirability of surgery is 72% (21/29). Of the 74 patients with a normal ejection fraction and complete follow-up, eight are known to have responded to surgery and 1 0 remain symptomatic without specific treatment. The specificity of the ejection fraction therefore lies between 89% (66/74) and 76% (56/74). Given sensitivity and specificity values in that range, cholecystokinin-stimulated cholescmntigraphy should be used only in a highly selected population of patients with chronic pain typical of biliary disease. It remains to be confirmed whether the positive clinical response in patients who have had surgery reflects the inherent value of cholescintigraphy or the clinical judgment in the selection of patients for surgery from the group with low ejection fractions. ACKNOWLEDGMENT We thank Jean Nyhus for secretarial assistance. REFERENCES 1. Cooperberg PL, Gibney RG. Imaging of the gallbladder, Radio!ogy 1987:163: Loberg MD, Nunn AD, Porter DW. Development of hepatobiliary imaging agents. In: Freeman LM, Weissman HS, eds. Nuclear medicine annual. New York: Raven, 1981: Pomeranz IS, Logan KJ, Shaffer EA. The adherence of Tc-DlSlDA to gallstones and gallbladder wall. J Nuc! Med Ailed Sci 1984:28: Krishnamurthy GT, Bobba vr, Kingston E. Radionuclide ejection fraction: a technique for quantitative analysis of motor function of the human gallbladder. Gastroentero!ogy 1981;80: Masclee MM, Jansen JBMJ, Corstens FHM, Lamers CBHW. Reversible gallbladder dysfunction in severe pancreatic insufficiency. Gut 1989; 30: Maton PN, Selden AC, Fitzpatrick ML, Chadwick VS. Defective gallbladder emptying and cholecystokinin release in celiac disease: reversal by glutenfree diet. Gastroentero!ogy 1985;88: Spellman SJ, Shaffer EA, Rosenthall L. Gallbladder emptying in response to cholecystokinin: a cholescintigraphic study. Gastroenterology 1979; 77: Maton PN, Selden AC, Fitzpatrick ML, Chadwick VS. Infusion of cholecystokinin octapeptide in man: relation between plasma cholecystokinin concentrations and gallbladder emptying rates. Eur J Clln invest 1984;14: Sarva RP, Shreiner DP, Van Thiel D, Yingvorapant N. Gallbladder function: methods for measuring filling and emptying. J Nuc! Med 1985;26: Hopman WPM, Jansen JBMJ, Rosenbusch G. Gallbladder contraction induced by cholecystokinin: bolus injection or infusion. BMJ 1986; 292: Worobetz U, Baker RJ, McCallum JA, Wells G, Sullivan SN. The effect of naloxone, morphine, and an enkephalin analogue on cholecystokinin octapeptide-stimulated gallbladder emptying. Am J Gastroentero! 1982; 77: Takahashi T, Yamamura T, Yokoyama E, et al. Impaired contractile motility of the gallbladder after gastrectomy. Am J Gastroentero! 1986;81: Parkin GJS, Smith RB, Johnston D. Gallbladder volume and contractility after truncal, selective and highly selective (parietal cell) vagotomy in man. Ann Surg 1973;178: Baxter JN, Grime JS, Critchley M, Jenkins SA, Shields R. Relationship between gastric emptying of a solid meal and emptying of the gallbladder before and after vagotomy. Gut 1987;28: Gullo L, Bolondi L, Priori P, Casanova P, Labo G. Inhibitory effect of atropine on cholecystokinin-induced gallbladder contraction in man. Digestion 1984:29: Fisher RS, Rock E, Malmud LS. Cholinergic effects on gallbladder emptying in humans. Gastroentero!ogy 1985;89: Crochelt RF, Peikin SR. Effect of nifedipine and extracellular calcium on spontaneous and potassium-stimulated bovine gallbladder muscle contraction (abstr.). Gastroentero!ogy 1987;92 : Malagelada JR. Holtermuller KH, Sizemore GW, Go VLW. The influence of hypercalcemia on basal and cholecystokinin-stimulated pancreatic, gallbladder, and gastric functions in man. Gastroentero!ogy 1976;71 : Waldman DB, Zfass AM, Makhlouf GM. Stimulatory (H1) and inhibitory (H2) histamine receptors in gallbladder muscle. Gastroenterology 1977;72: Mitsukawa T, Takemura J, Ohgo 5, et al. Gallbladder function and plasma cholecystokinin levels in diabetes mellitus. Am J Gastroentero! 1990; 85: Kronert K, Gotz V, Reuland P, Luft D, Eggstein M. Gallbladder emptying in diabetic patients and control subjects assessed by real-time ultrasonography and cholescintigraphy: a methodological comparison. Ultrasound Med Bid 1989;1 5: Everson GT, Nemeth A, Kourourian S. et al. Gallbladder function is altered in sickle hemoglobinopathy. Gastroenterology 1989:96: Vezina WC, Paradis RL, Grace DM, et al. Increased volume and decreased emptying of the gallbladder in large (morbidly obese, tall normal and muscular normal) people. Gastroenterology 1990;98: Kellow JE, Miller U, Philips SF, Zinsmeister AR, Charboneau JW. Altered sensitivity ofthe gallbladderto cholecytokinin octapeptide in irritable bowel syndrome. Am J Physiol 1987;253:G650-G KhaliI T, Walker JP, Wiener I, et al. Effect of aging on gallbladder contraction and release of cholecystokinin-33 in humans. Surgery 1985;98: Shaffer EA, Taylor PJ, Logan K, Gadomski 5, Corenblum B. The effect of a progestin on gallbladder function in young women. Am J Obstet Gynecol 1984;148: Raptopoulos V, Compton CC, Doherty P. et al. Chronic acalculous gallbladder disease: multiimaging evaluation with clinical-pathologic correlation. AJR 1986;147: Thompson JC, Fried GM, Ogden WD, et al. Correlation between release of cholecystokinin and contraction of the gallbladder in patients with gallstones. Ann Surg 1982;195: Fisher RS, Stelzer F, Rock E, Malmud LS. Abnormal gallbladder emptying in patients with gallstones. Dig Dis Sci 1982;27: Fridhandler TM, Davison JS, Shaffer EA. Defective gallbladder contractility in the ground squirrel and prairie dog during the early stages of cholesterol gallstone formation. Gastroenterology 1983;85: Behar J, Lee KY, Thompson WR, Biancani P. Gallbladder contraction in

5 AJR:159, September 1992 CHOLECYSTOKININ CHOLESCINTIGRAPHY FOR BILIARY PAIN 513 patients with pigment and cholesterol stones. Gastroenterology 1989; 97: Brugge WA, Brand DL, Atkins HL, Lane BP, Abel WG. Gallbladder dyskinesia in chronic acalculous cholecystitis. Dig Dis Sci 1986;31 : Masclee AAM, Jansen JBMJ, Driessen WMM, Geuskens LM, Lamers CBHW. Plasma cholecystokinin and gallbladder responses to intraduodenal fat in gallstone patients. Dig Dis Sci 1989:34: Pomeranz IS, Shaffer EA. Abnormal gallbladder emptying in a subgroup of patients with gallstones. Gastroenterology 1985;88: Raymond F, Lepanto L, Rosenthall L, Fried GM. Tc-99m IDA gallbladder kinetics and response to CCK in chronic cholecystitis. Eur J Nuc! Med 1988;14: Grade WA, Ransohoff DF. The natural history of silent gallstones: the innocent gallstone is not a myth. N Eng! J Med 1982;307: Cozzolino HJ, Goldstein F, Greening AR, Wirts CW. The cystic duct syndrome. JAMA 1963;185: Nathan MH, Newman A, Murray DJ. Normal findings in oral and cholecystokinin cholecystography. JAMA 1978;240: Dunn FH, Christensen EC, Reynolds J, Jones V. Fordtran JS. Cholecystokinin cholecystography: controlled evaluation in the diagnosis and management of patients with possible acalculous gallbladder disease. JAMA 1974:228: New Format for Abstracts 40. Davis GB, Berk RN, Scheible FW, et al. Cholecystokinin cholecystography, sonography, and scintigraphy: detection of chronic acalculous cholecystitis.ajr 1982;139: Westlake PJ, Hershfield NB, Kelly JK, et al. Chronic right upper quadrant pain without gallstones: does HIDA scan predict outcome after cholecystectomy? Am J Gastroenterol 1990:85: Pickleman J, Peiss AL, Henkin A, Sale B, Nagel P. The role of sincalide cholescintigraphy in the evaluation of patients with acalculous gallbladder disease. Arch Surg 1985;120: Fink-Bennett D, DeAidder P, Kolozsi W, Gordon A, AappJ. Cholecystokinin cholescintigraphic findings in the cystic duct syndrome. J Nuc! Med 1985;26: Topper TE, Ryerson TW, Nora PF. Quantitative gallbladder imaging following cholecystokinin. J NucI Med 1980;21 : Ahind JA, Watson L. Gall stone dyspepsia. BMJ 1968;1 : Gunn A, Keddie N. Some clinical observations on patients with gallstones. Lancet 1972;2: Yap L, Wycherley AG, Morphett AD, Toouli J. Acalculous biliary pain: cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology 1991;101 : Beginning immediately, the AJR will publish abstracts of articles in a different format, much like the ones recently adopted by the New England Journal of Medicine and the Journal of the American MedicalAssociation. The purpose of the new design is to have abstracts present the essential elements of articles more clearly and concisely. The contents, organization, and length of the abstracts will be the same as before; however, rather than being all one paragraph except for the conclusion, abstracts will now be divided into four paragraphs, each with a title: objective, subjects (or materials) and methods, results, and conclusion. The AJR Guidelines for Authors, which appears at the front of every issue of the Journal, has been revised to help you write abstracts in this new format. Authors should familiarize themselves with these guidelines and incorporate them into all manuscripts submitted for publication. Robert N. Berk Editor-in-Chief