Journal of Nuclear Medicine, published on April 17, 2014 as doi:10.2967/jnumed.113.131490 Hepatobiliary Scintigraphy in 2014 Harvey A. Ziessman Division of Nuclear Medicine, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institute, Baltimore, Maryland Learning Objectives: On successful completion of this activity, participants should be able to describe (1) diagnostic uses of hepatobiliary scintigraphy; (2) proper methodology for performing cholescintigraphy for various clinical indications; (3) pharmacologic interventions; and (4) image interpretative criteria to make clinical diagnoses. Financial Disclosure: The author of this article has indicated no relevant relationships that could be perceived as a real or apparent conflict of interest. CME Credit: SNMMI is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNMMI designates each JNM continuing education article for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, participants can access this activity through the SNMMI website (http:// www.snmmi.org/ce_online) through June 2017. simply that of 2 lidocaine analogs bichelated to 99mTc by iminodi- Cholescintigraphy with 99mTc-hepatobiliary radiopharmaceuticals has acetic acid (IDA) (Fig. 2). HIDA (hepatoiminodiacetic acid) has long ½Fig: 2 been an important, clinically useful diagnostic imaging study for al- been used as a generic term for cholescintigraphy. most 4 decades. It continues to be in much clinical demand; however, Modifications of the benzene ring of the lidocaine analogs resulted the indications, methodology, and interpretative criteria have evolved in an alphabet soup of hepatobiliary radiopharmaceuticals (PIPIDA, over the years. This review will emphasize state-of-the-art methodol- BIDA, EIDA, DIDA, DISIDA, etc.), each with different rates of ogy and diagnostic criteria for various clinical indications, including hepatic uptake and clearance. The first 99mTc-HIDA radiopharma- acute cholecystitis, chronic acalculous gallbladder disease, high- ceutical was approved for clinical use by the Food and Drug grade and partial biliary obstruction, and the postcholecystectomy pain syndrome, including sphincter-of-Oddi dysfunction and biliary Administration in 1982. Dimethyl IDA (lidofenin [Technescan; atresia. The review will also emphasize the use of diagnostic phar- Mallinckrodt]) was a major advance, but image quality and di- macologic interventions, particularly sincalide. agnostic utility were suboptimal in patients with serum bilirubin Key Words: hepatobiliary scintigraphy; cholescintigraphy; acute levels above 5.0 mg/dL. It is no longer available. 99m cholecystitis; chronic cholecystitis; chronic acalculous gallbladder In 1986, the Food and Drug Administration approved Tc- disease; biliary dyskinesia disofenin (diisopropyl-IDA [Hepatolite; Pharmalucence]). It pro- vided images of diagnostic quality with bilirubin levels of as high J Nucl Med 2014; 55:1–9 99m DOI: 10.2967/jnumed.113.131490 as 25–30 mg/dL. In 1993, Tc-mebrofenin (bromotriethyl-IDA [Choletec; Bracco]) was approved. It had higher liver extraction (98% vs. 89%) and more rapid biliary clearance than 99mTc- disofenin (half-life of 19 min vs. 17 min). After intravenous injection, 99mTc-HIDA radiopharmaceuticals are transported in the blood bound to serum albumin. They disso- 99m Now almost 4 decades old, Tc cholescintigraphy continues ciate from albumin in the hepatic perisinusoidal space and are to be a radionuclide imaging study in much clinical demand. Its extracted by hepatocytes by receptor-mediated endocytosis, similar strength lies in the fact that the diagnostic information provided to bile salts, free fatty acids, and bilirubin. They then follow the same defines pathophysiology rather than anatomy. metabolic pathway as bilirubin, except that they are secreted into 123 123 I- and I-rose bengal were the first clinically useful chole- biliary caliculi unchanged, without undergoing conjugation. scintigraphic agents; however, image quality was relatively poor This review will emphasize modern-day use and newer develop- ½ : 99m Fig 1 (Fig. 1). Tc-hepatobiliary radiopharmaceuticals began to be ments that affect clinical practice. Space does not permit review of widely used by the early 1980s. all of the many clinical indications for cholescintigraphy (i.e., 99m The discovery of Tc-hepatobiliary (HIDA) radiopharmaceuti- acute cholecystitis, chronic cholecystitis, acute biliary obstruction, cals was by chance. During investigation for a cardiac imaging ra- partial biliary obstruction, sphincter-of-Oddi dysfunction, biliary 99m diopharmaceutical, it was found that Tc-labeled lidocaine was atresia, biliary leak, biliary stent patency, enterogastric bile reflux, not a good cardiac imaging agent but cleared through the hepatobili- complications from the biliary diversion procedure, complications 99m ary system. With chemical modification, Tc-HIDA imaging agents after liver transplantation, differential diagnosis of hepatic tumors, were born. Loberg et al. reported on this in 1976 (1). Its structure is and prediction of remnant liver function after partial hepatectomy). ACUTE CHOLECYSITIS Received Dec. 3, 2013; revision accepted Mar. 3, 2014. For correspondence or reprints contact: Harvey A. Ziessman, Johns Acute cholecystitis is the most common clinical indication for Hopkins Medical Institute, John Hopkins Outpatient Center, 601 N. Caroline St., Suite 3231, Baltimore, MD 21278. cholescintigraphy. Patients present with acute colicky pain in the E-mail: [email protected] right upper quadrant lasting hours or days. Except for low-grade Published online ▪▪▪▪▪▪▪▪▪▪▪▪. COPYRIGHT © 2014 by the Society of Nuclear Medicine and Molecular fever and a moderately elevated leukocyte count, laboratory Imaging, Inc. findings (including liver function studies) are usually normal. A HEPATOBILIARY SCINTIGRAPHY IN 2014 • Ziessman 1 jnm131490-sn n 4/9/14 cholecystitis, only a few have directly compared the relative accuracy of sonography and cholescintigraphy in the same investigation. Six of 7 direct-comparison published investigations have shown superior accuracy for cholescintigraphy over sonog- raphy (Table 1) (5–11). CT and MR are most useful for detection ½Table 1 of suspected complications. Cholescintigraphy demonstrates the primary underlying patho- physiology of acute cholecystitis, that is, obstruction of the cystic duct, and thus the 99mTc-HIDA radiopharmaceutical cannot enter the gallbladder. Stones are the cause of obstruction in more than 90% of patients, but stones are rarely visualized by anatomic imaging because of their small size and the sonographic acoustic problems in the small cystic duct. Patient Preparation 123 99m FIGURE 1. I-rose bengal cholescintiscan (left) and Tc-HIDA Patients should ingest nothing by mouth for 3–4 h before in- cholescintiscan (right). jection of the 99mTc-HIDA radiopharmaceutical. This interval few patients will have an elevated level of serum bilirubin caused allows time for the ingested meal to have passed though the prox- by stones lodged in both the cystic and the biliary ducts or, less imal small bowel, where fat stimulates endogenous cholecystoki- commonly, by an impacted cystic-duct stone compressing the nin release and thus gallbladder contraction, and then time for the adjacent hepatic or common bile duct (Mirizzi syndrome). gallbladder to relax. When patients are interviewed about when A sequence of pathophysiologic events occurs with acute chole- they last ate, a question on what they ate is helpful. A meal with at cystitis. Initially the cystic duct is obstructed, usually by a stone. The least 10 g of fat is required to contract and empty the gallbladder. gallbladder mucosa becomes edematous, followed by neutrophilic Patients who have been fasting for more than 24 h have had no infiltration, then mucosal ulceration, hemorrhage, and necrosis, stimulation to contract the gallbladder and will likely have concen- and ultimately, if left untreated, the complications of perforation, trated viscous jellylike bile that can prevent entry of radiotracer and gangrene, and abscess (2). result in a false-positive study for acute cholecystitis. In these patients, sincalide (Kinevac; Bracco) should be administered before Ultrasonography the study to empty the gallbladder. The pharmacologic dose (0.02 Ultrasonography is often part of the initial work-up for suspected mg/kg) should be infused over 60 min, similar to what is described hepatobiliary disease. It is readily available, does not use ionizing later in this review for optimal gallbladder contraction. However, radiation, and can detect various intraabdominal diseases in addition some patients with chronic cholecystitis may have poorly con- to acute cholecystitis, such as biliary obstruction, pancreatitis, and tracting gallbladders and thus not respond to the sincalide, result- tumors. ing in a false-positive study. The 99mTc-HIDA agent should be The sonographic findings of acute cholecystitis are usually injected at least 30 min later to provide sufficient time for gallblad- nonspecific and secondary pathologic findings. Gallstones are present der relaxation. in most patients with acute cholecystitis; however, because choleli- thiasis is common in the general population and often remains Scintigraphic Protocol asymptomatic for a lifetime, its presence