Hepatobiliary Scintigraphy: - PDF Free Download

Cholecystokinin-Augmented Hepatobiliary Scintigraphy: Dissecting the Art from Science Mark Tulchinsky, MD, FACNP Professor of Radiology and Medicine Penn State University College of Medicine Hershey, Pennsylvania mtulchin@psu.edu

Educational Goals Gallbladder (GB) diseases referred for cholecistokinin-augmented hepatobiliary scintigraphy (CCK-HBS) Basic science of CCK-HBS Basic science of GB Ejection Fraction (GBEF) Spectrum of methodology Current investigational frontier of CCK-HBS Case-based review the art of imaging Pearls optimizing i i image-based diagnosis i Pitfalls what to avoid and watch out for

Introduction: Clinical Spectrum Calculous cystic duct obstruction = GB non-vis Acalculous most have obstructed cystic duct and non- visualization of GB. Some fill in the GB, but response to cholecystokinin (CCK) is abnormal dyskinesia Acute cholecystitis Abd/p, GB non-vis or visualized, but demonstrates dyskinesia i Chronic cholecystitis Abd/p, GB dyskinesia Calculous Acalculous Functional GB pain Abd/p, GB dyskinesia SOD Abd/p, GB dyskinesia Abd/p = abdominal pain; non-vis. = non-visualization; SOD = Sphincter of Oddi Dysfunction.

Introduction: Clinical Presentation Chronic disease (including functional) often atypical clinical presentation: Patients often referred for numerous expensive anatomical imaging procedures, often negative, over a long period of time Stones in the GB may or may not be present GB dysfunction is the key diagnostic finding Surgery, cholecystectomy, is the only treatment option (except in SOD), but can we predict who will benefit? SOD = Sphincter of Oddi Dysfunction

Radiopharmaceuticals Proposed bis structure of 99m Tc-IDAs Lidofenin (HIDA) Disofenin (DISIDA) Mebrofenin (BromIDA) [[(2,6-Xylylcarbamoyl) [[(2,6-Diisopropylphenyl)carbamoyl] [[[(3-Bromomesityl)carbamoyl] methyl]-imino]diacetic acid -imino]diacetic acid Methyl]-imino]diacetic acid NCBI PubChem. http://pubchem.ncbi.nlm.nih.gov/

Uptake of IDA is facilitated by carrier-mediated, non-sodium dependent, organic Uptake anionic pathway of IDA similar to bilirubin Radiopharmaceutical delivered via hepatic artery (25%) and portal vein (75%)

Uptake of IDA IDA ( ) Radiopharmaceutical extracted by hepatocytes and transported without modification

Hepatobiliary Scintigraphy: Imaging Sequence Blood flow imaging, first minute optional Baseline one-hour dynamic imaging depicts parenchymal uptake, bile excretion, and passage Postintervention dynamic imaging, g, carried out for at least 30 minutes, depicts response to CCK, morphine, etc Delayed static images as needed can be carried out for up to 24 hours

HBS: Digital Set-Up 128x128x16 matrix 60 minute dynamic acquisition, anterior (posterior is optional) projection Dynamic acquisition 15-30 s/frame Display in 15 frames (4 min/frame) Acquire dynamically for at least 30 min after intervention ti (morphine, CCK, etc) Display in 15 frames (2 min/frame) Tulchinsky M. Hepatobiliary Scintigraphy. In: Diagnostic Nuclear Medicine, 2nd revised edition. Published 2005 Springer

Anterior View

40 o Left Anterior Oblique View Makes Good Anatomical Sense

40 o LAO Projection 2 min/frame 30 minutes Post CCK 2 min/frame

40 o LAO Separates GB from Duodenal Activity

Gallbladder Ejection Fraction Determination Stimulus: Cholecystokinin-8 (sincalide) IV Fatty meal GBEF calculation: Net GB counts max Net GB counts min Net GB counts max x 100% The Society of Nuclear Medicine Procedure Guideline for Hepatobiliary cholescintigraphy. Accessed September 1, 2007 at: http://interactive.snm.org/docs/pg_ch11_0703.pdf

Fasting Postprandial or Post-CCK Costoff A. Gastrointestinal Physiology: Biliary Secretion and Excretion. http://www.lib.mcg.edu/edu/eshuphysio/program/section6/6ch5/s6ch5_12.htm

Effects of Two Different Doses of CCK on GBEF and Refilling CCK-8 Dose GB visualized GBEF % Refilled GB at time (min): (min) (%) 20 30 40 50 Group A 0.02 µg/kg/3 min 20 ± 2 35 ± 17 50 83 83 100 (n = 6) Group B 0.04 µg/kg/3 min 21 ± 10 43 ± 26 25 50 63 63 (n = 12) Group A + B 21 ± 8 40 ± 23 33 63 71 79 Values expressed as mean ± one standard deviation Mesgarzadeh M, Krishnamurthy GT, Bobba VR, Langrell K. Filling, postcholecystokinin emptying, and refilling of normal gallbladder: effects of two different doses of CCK on refilling: concise communication. J Nucl Med. Aug 1983;24(8):666-671.

Gallbladder Disease Responsible for Abdominal Pain/Biliary Colic CCK infusion technique has to be tested in normal individuals to determine normal GBEF range A threshold GBEF should identify abnormal function, dyskinesia, based on EF that is outside the normal range The threshold GBEF should accurately triage patients into: those who will benefit from surgery (below GBEF threshold) those who will not benefit from surgery

Chronic Gallbladder or Biliary Disease: Spectrum of Conditions Biliary dyskinesia Gallbladder dyskinesia Chronic acalculous cholecystitis Chronic acalculous biliary disease Acalculous biliary disease Cystic duct syndrome Gallbladder spasm Sphincter of Oddi dysfunction

GBEF Clinical symptoms and signs allow selection of patients for surgery with 70% accuracy Low GBEF measurement assists in identification of those who will sustain symptomatic ti improvement after cholecystectomy with an accuracy of 95% GBEF = gallbladder ejection fraction Zech ER, Simmons LB, Kendrick RR, et al. Cholecystokinin enhanced hepatobiliary scanning with ejection fraction calculation as an indicator of disease of the gallbladder. Surg Gynecol Obstet. Jan 1991;172(1):21-24.

Ideal GBEF Test Ideally, a stimulus should elicit the highest possible GBEF, making abnormal GBEF easier to identify. Ideally, the normal response should be consistent (a narrow standard deviation). Ideally, the time to obtain the highest GBEF should be clinically practical. GBEF threshold should be tested in the target population by a prospective, randomized, controlled clinical trial.

Normal Values Min/µg per kg (Ref.) GBEF (M±S.D.) Range n 1/0.02 (3) 52±42% 12-92% 22 3/0.04 (1) 43±26% 15-88% 12 3/0.02 (1) 35±17% 17-59% 6 3/0.02 (5) 56±27% 0-100% 23 3/0.01 (4) 46±20% 12-74% 20 10/0.01 (6) 76±16% 37-96% 13 15/0.02 (2) 76±22% 32-98% 15 30/0.01 (5) 64±20% 26-95% 14 30/0.02 (5) 70±22% 17-97% 23 45/0.015 (3) 77±23% 65-96% 22 45/0.015 015 (7) 75±12% >40% 40 60/0.01 (4) 68±16% 15-88% 20 patients rather than normal volunteers 1. Mesgarzadeh M, Krishnamurthy GT, et al. J Nucl Med. 1983; 24 (8):666-71. 2. Raymond F, Lepanto L, Rosenthall L et al. Eur J Nucl Med. 1988; 14 (7-8):378-81. 99% confidence limits 3. Sarva RP, Shreiner DP, Van Thiel D et al. J Nucl Med. 1985; 26 (2):140-4. 4. Ziessman HA, Muenz LR, Agarwal AK et al. Radiology. 2001; 221 (2):404-10. 5. Ziessman HA, Fahey FH, Hixson DJ. J Nucl Med. Apr 1992;33(4):537-541. 6. Krishnamurthy GT, Brown PH. J Nucl Med. Dec 2002;43(12):1603-1610. 7. Yap L, et. al. Gastroenterology. Sep 1991;101(3):786-793.

Fatty Meal vs. CCK? CCK1 = 75.8 ± 16.3% CCK2 = 71.3 ± 17.4% MEAL = 53.6 ± 20.2% Excluded were 8/21 prescreened because GBEF <35% after 3 minute injection Krishnamurthy GT, et al. J Nucl Med. 2002;43:1603-1610.

Pre-treating with CCK Doesn t Influence CCK-GBEF Krishnamurthy GT, Brown PH. Comparison of fatty meal and intravenous cholecystokinin infusion for gallbladder ejection fraction. J Nucl Med. Dec 2002;43(12):1603-1610 1610. Sostre S, Canto MI, Kalloo AN. Gallbladder response to a second dose of cholecystokinin during the same imaging study. Eur J Nucl Med. 1992;19(11):964-965. Single dose CCK, GBEF 70±20% Second dose CCK, GEBE 71.5±19%

Variability of Emptying Curves: Fatty Meal

Benefit of CCK Stimulation CCK injection has a more predictable rate of GB contraction Maximum GB emptying occurs shortly (within few minutes) after infusion ends predictable time for minimum GB counts Fatty meal has an unpredictable rate of GB contraction It takes longer to reach maximum contraction harder to know when to expect minimum GB counts Krishnamurthy GT, et al. J Nucl Med. 2002;43:1603-1610. Krishnamurthy GT, et al. J Nucl Med. 2004;45:1872-1877.

Does the Fatty Meal have Ideal Science to Support it? Ideally, a stimulus should elicit the highest possible GBEF, making abnormal GBEF easier to identify. Ideally, the normal response should be consistent (a narrow standard deviation). Ideally, the time to obtain the highest h GBEF should be clinically practical. GBEF threshold should be tested in the target population by a prospective, randomized, d controlled clinical i l trial.

IV Bolus versus 45 Min Infusion GBEF (1 min) = 52±42% GBEF (45 min) = 77±23% Sarva RP, Shreiner DP, Van Thiel D, Yingvorapant N. Gallbladder function: methods for measuring filling and emptying. J Nucl Med. Feb 1985;26(2):140-144.

CCK Administration (0.01 mcg/kg) 3 Minutes vs. 60 Minutes Infusion 3 min 60 min infusion 35% 15 min 30 min 45 min 60 min

CCK 3-Minute Injection 27 asymptomatic subjects Sincalide 0.02 mcg/kg over three minutes Imaged in anterior projection Two incalculable (bowel overlap) 9 GBEF > 35% 16 GBEF < 35% Fink-Bennett D, et al. J Nucl Med. 1991;32:1695-1699.

GB Neck Spasm: IV Push of CCK

Short, 1-5 min (most 3 min) Sincalide Infusion: Supporting Literature All Retrospective ± 1. Pickleman J, Peiss RL, Henkin R, Salo B, Nagel P. The role of sincalide cholescintigraphy in the 2. + evaluation of patients with acalculus gallbladder disease. Arch Surg. Jun 1985;120(6):693-697. Fink-Bennett D, DeRidder P, Kolozsi WZ, Gordon R, Jaros R. Cholecystokinin cholescintigraphy: detection of abnormal gallbladder motor function in patients with chronic acalculous gallbladder 3. + disease. J Nucl Med. Sep 1991;32(9):1695-1699. Misra DC, Jr., Blossom GB, Fink-Bennett D, Glover JL. Results of surgical therapy for biliary dyskinesia. Arch Surg. Aug 1991;126(8):957-960. 4. Zech ER, Simmons LB, Kendrick RR, et al. Cholecystokinin enhanced hepatobiliary scanning with ± ejection fraction calculation as an indicator of disease of the gallbladder. Surg Gynecol Obstet. Jan 1991;172(1):21-24. 5. Middleton GW, Williams JH. Is gall bladder ejection fraction a reliable predictor of acalculous gall + bladder disease? Nucl Med Commun. Dec 1992;13(12):894-896. 6. Sorenson MK, Fancher S, Lang NP, Eidt JF, Broadwater JR. Abnormal gallbladder nuclear ejection + fraction predicts success of cholecystectomy in patients with biliary dyskinesia. Am J Surg. Dec 1993;166(6):672-674; discussion 674-675. 7. Khosla R, Singh A, Miedema BW, Marshall JB. Cholecystectomy alleviates acalculous biliary pain in + patients with a reduced gallbladder ejection fraction. South Med J. Nov 1997;90(11):1087-1090. 8. Goncalves RM, Harris JA, Rivera DE. Biliary dyskinesia: natural history and surgical results. Am Surg. + Jun 1998;64(6):493-497; 497; discussion 497-498. 498 9. Mishkind MT, Pruitt RF, Bambini DA, et al. Effectiveness of cholecystokinin-stimulated cholescintigraphy in the diagnosis and treatment of acalculous gallbladder disease. Am Surg. Sep 1997;63(9):769-774. 10. Klieger PS, O'Mara RE. The clinical utility of quantitative cholescintigraphy: the significance of + gallbladder dysfunction. Clin Nucl Med. May 1998;23(5):278-282. 11. Frassinelli P, Werner M, Reed JF, 3rd et al. Laparoscopic cholecystectomy alleviates pain in patients with acalculous biliary disease. Surg Laparosc Endosc. 1998; 8 (1):30-4.

Short, 1-5 min (most 3 min) Sincalide Infusion: Supporting Literature All Retrospective + 12. Middleton GW, Williams JH. Diagnostic accuracy of 99Tcm-HIDA with cholecystokinin and gallbladder ejection fraction in acalculous gallbladder disease. Nucl Med Commun. Jun 2001;22(6):657-661. 13. Al-Homaidhi HS, Sukerek H, Klein M, Tolia V. Biliary dyskinesia in children. Pediatr Surg Int. Sep + 2002;18(5-6):357-360. 14. Bingener J, Richards ML, Schwesinger WH, Sirinek KR. Laparoscopic cholecystectomy for biliary dyskinesia: correlation of preoperative cholecystokinin cholescintigraphy results with postoperative + outcome. Surg Endosc. May 2004;18(5):802-806. 15. Sabbaghian MS, Rich BS, Rothberger GD, et al. Evaluation of surgical outcomes and gallbladder + characteristics in patients with biliary dyskinesia. J Gastrointest Surg. Aug 2008;12(8):1324-1330. 16. Constantinou C, Sucandy I, Ramenofsky M. Laparoscopic cholecystectomy for biliary dyskinesia in + children: report of 100 cases from a single institution. Am Surg. Jul 2008;74(7):587-592; discussion 593.

Does Scientific Evidence Support Short Infusion Sincalide Test? Ideally, a stimulus should elicit the highest possible GBEF, making abnormal GBEF easier to identify. Ideally, the normal response should be consistent (a narrow standard deviation). Ideally, the time to obtain the highest h GBEF should be clinically practical. GBEF threshold should be tested in the target population by a prospective, randomized, controlled clinical trial.

Sincalide 10 Min. (Intermediate) Infusion Technique Sincalide 0.01 µg/kg over 10 minutes 13 healthy subjects 75.8±16.3% first injection 71.3±17.4% second injection Krishnamurthy GT, et al. J Nucl Med. 2002;43:1603-1610.

Does Scientific Evidence Support 10 Min Infusion Sincalide Test? Ideally, a stimulus should elicit the highest possible GBEF, making abnormal GBEF easier to identify. Ideally, the normal response should be consistent (a narrow standard deviation). Ideally, the time to obtain the highest h GBEF should be clinically practical. GBEF threshold should be tested in the target population by a prospective, randomized, controlled clinical trial.

Sincalide 15 Min. (Intermediate) Infusion Technique Sincalide (CCK) 0.02 mcg/kg, we use an automated syringe pump to infuse Acquire for 30 minutes Detector typically positioned at 35-40 o in the left anterior oblique projection Threshold GBEF: + + adult 35% pediatric 50% Dumont RC, et al. J Pediatr Surg. 1999;34:858-8661; 8661; discussion 8661-862. Poynter MT, et al. Am Surg. 2002;68:382-384.

GBEF Range (cholecystokinin-8, 0.02 µg/kg, 15 min.) Chronic Cholecystitis all had stones and fibrosis on pathology Control A abdominal pain of nonbiliary etiology Control B normal volunteers 56.4% 27.5% 76.4% 22.2% 72.9% 17.3% 74.8% 19% 35% Raymond F, Lepanto L, Rosenthall L, et al: Tc-99m-IDA gallbladder kinetics and response to CCK in chronic cholecystitis. Eur J Nucl Med (1988) 14:378-81 (McGill U)

Does Scientific Evidence Support 15 Min Infusion Sincalide Test? Ideally, a stimulus should elicit the highest possible GBEF, making abnormal GBEF easier to identify. Ideally, the normal response should be consistent (a narrow standard deviation). Ideally, the time to obtain the highest h GBEF should be clinically practical. GBEF threshold should be tested in the target population by a prospective, randomized, controlled clinical trial.

Sincalide 30 min/0.02 µg/kg (Long) Infusion 1. 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. Aug 1990;85(8):986-990. 2. Majeski J. Gallbladder ejection fraction: an accurate evaluation of symptomatic acalculous gallbladder disease. Int Surg. Apr-Jun 2003;88(2):95-99.

Does Scientific Evidence Support 30 Min Infusion Sincalide Test? Ideally, a stimulus should elicit the highest possible GBEF, making abnormal GBEF easier to identify. Ideally, the normal response should be consistent (a narrow standard deviation). Ideally, the time to obtain the highest h GBEF should be clinically practical. GBEF threshold should be tested in the target population by a prospective, randomized, controlled clinical trial.

Sincalide 45 Min. Infusion (Long): Supporting Literature Yap L, Wycherley AG, Morphett AD, et al. Acalculous biliary pain: cholecystectomy t alleviates symptoms in patients t with abnormal cholescintigraphy. Gastroenterology. 1991;101(3):786-793. (The only randomized, prospective study) Watson A, Better N, Kalff V, et al. Cholecystokinin (CCK)- HIDA scintigraphy in patients with suspected gallbladder dysfunction. Australas Radiol. 1994;38(1):30-33. Gani JS. Can sincalide cholescintigraphy fulfil the role of a gall-bladder stress test for patients with gall-bladder stones? Aust N Z J Surg. Jul 1998;68(7):514-519. Sabbaghian MS, Rich BS, Rothberger GD, et al. Evaluation of surgical outcomes and gallbladder characteristics in patients with biliary dyskinesia. J Gastrointest Surg. Aug 2008;12(8):1324-1330. 1330

45 min Infusion Technique: Dose Escalation Study Sarva RP, Shreiner DP, Van Thiel D, Yingvorapant N. Gallbladder function: methods for measuring filling and emptying. J Nucl Med. Feb 1985;26(2):140-144.

Does Scientific Evidence Support 45 Min Infusion Sincalide Test? Ideally, a stimulus should elicit the highest possible GBEF, making abnormal GBEF easier to identify. Ideally, the normal response should be consistent (a narrow standard deviation). Ideally, the time to obtain the highest h GBEF should be clinically practical. GBEF threshold should be tested in the target population by a prospective, randomized, controlled clinical trial.

Does Scientific Evidence Support 60 Min (Long) Sincalide Infusion? Ideally, a stimulus should elicit the highest possible GBEF, making abnormal GBEF easier to identify. Ideally, the normal response should be consistent (a narrow standard deviation). Ideally, the time to obtain the highest h GBEF should be clinically practical. GBEF threshold should be tested in the target population by a prospective, randomized, controlled clinical trial.

The New Frontier of CCK-HBS Research Establish which infusion protocol has the least variability in GBEF: 0.02 µg/kg over 15 min 002 0.02 µg/kg over 30 min 0.02 µg/kg over 45/60 min Evaluate the methods in healthy individuals 60 volunteers The next step would be to take the best infusion method and test it in a randomized controlled clinical trial

Preparation for the Hepatobiliary Examination Exclude the use of opioids (four half lives of a drug) Obtain history of gallbladder disease or surgery Instruct to have a fatty snack at 8-9 PM Fasting after the snack Pre-treat with CCK if NPO longer than 24 hours Schedule for early AM imaging

Outside Hospital Study: Referred for Consult Anterior View 20070123

Outside Hospital Study: Referred for Consult 20070123

The Consult Delayed appearance of activity in the gallbladder is consistent with chronic cholecystitis Our concerns: Patient did not receive clear instructions about meal preparation to facilitate t gallbladder visualization, just fasted after midnight No CCK stimulation to define gallbladder function

Anterior View 20070207 Rt. Lat.

LAO View 20070207

20070207

Anterior View

LAO View

RAO Position Example Anterior View

RAO Position Example LAO 30% L. Lat

RAO Position Example LAO 35% LAO 40% LAO 45% LAO 25% LAO 20% LAO 15%

RAO Position Example Anterior RAO 15% RAO 20%

RAO Position Example RAO 20% View

RAO Position Example

Here is the question: Is the GBEF correct? Yes No Patient Motion Wrong Region

Summary HBS depicts hepatocyte function, bile formation, biliary transit to the GB and bowel HBS with CCK-GBEF should be interpreted based on the clinically validated criteria There is a choice of multiple CCK administration protocols When properly done, below the threshold CCK-GBEF identifies patients who are likely (>90% likelihood) to become free of their abdominal pain after cholecystectomy