Hepatobiliary Scintigraphy

Anatomy and Physiology

The biliary system consists of the gallbladder, ducts, and associated structures that are responsible for the production and transportation of bile. It starts when the liver hepatocytes generate and secrete bile into small tubular channels called biliary canaliculi.[7] These combine to form intralobular and then interlobular ducts. These bile ducts combine to create the left and right hepatic ducts which represent the beginning of the extrahepatic biliary tree. These ducts subsequently join to form the common hepatic duct which then combines with the cystic duct (from the gallbladder) forming the common bile duct. The common bile duct courses in the portahepatis, alongside the hepatic artery and portal vein, to join the pancreatic duct which enters the second portion of the duodenum through the ampulla of Vater, or hepatobiliary ampulla. The circular muscle surrounding the ampulla of Vater is the sphincter of Oddi which opens and closes the ampulla and hence controls the flow of bile into the small bowel.

Indications

Hepatobiliary scintigraphy evaluates the function of hepatocytes, patency, and integrity of the biliary ducts, gallbladder contractility, and sphincter of Oddi function. The following conditions can be evaluated using a hepatobiliary scintigraphy exam:

• Acute cholecystitis (calculous and acalculous)
• Chronic gallbladder disease (aka functional gallbladder disease or chronic cholecystitis)
• Biliary leak
• Biliary obstruction (to include stent patency and sphincter of Oddi dysfunction)
• Biliary atresia

Acute cholecystitis is one of the most common clinical indications for HBS exams.[8] Acute calculus cholecystitis results from gallstones and cystic duct obstruction and comprises more than 90 percent of all acute cholecystitis cases. The remaining 5 to 10 percent of acute cholecystitis cases are due to biliary stasis leading to acute acalculous cholecystitis which affects the very old, the very young, the critically ill (trauma, burn, and immunocompromised patients), and patients on total parenteral nutrition.[1]

A biliary leak can be seen following damage to the biliary system and is most common after cholecystectomy, liver procedures such as wedge resection or segmentectomy/lobectomy, transplantation, as well as hepatic trauma.

Biliary obstruction is seen in multiple scenarios to include choledocholithiasis, stricture, biliary or pancreatic tumor, and sphincter of Oddi dysfunction (SODD). 

Biliary atresia is a rare congenital disorder which can cause irreversible liver damage if not surgically corrected within the first 2 to 3 months of life. This surgery is a stop-gap measure allowing the child to grow and ultimately receive liver transplantation. HBS can be extremely useful for differentiating it from severe neonatal hepatitis which may cause a similar presentation of neonatal jaundice.[9]

Contraindications

Absolute contraindications to the radiotracer are very few and rare. History of severe anaphylactic reaction to the radiotracer is the only absolute contraindication.

Relative contraindications mainly concern patient preparation.

Various drugs may modulate the biliary system and therefore should be screened for before commencing the exam. The most commonly encountered interfering medications are the opiates, given that they are frequently used to treat patients' acute or chronic pain. Opiates, particularly morphine, cause increased tone in the sphincter of Oddi which results in a functional obstruction at the ampulla of Vater that can mimic a true anatomic obstruction. Thus, if there is clinical concern for biliary obstruction, opiates should be withheld for at least 6 hours prior to the exam to avoid a potential false-positive result. Similarly, opiates may decrease contractility of the gallbladder and thus should be withheld prior to the assessment for chronic gallbladder disease to avoid a spuriously low measured gallbladder ejection fraction.

Other medications associated with poor gallbladder contractility require an evaluation of the risk of medication modification or cessation before assessment for chronic gallbladder disease. These medications include[3]:

• Atropine
• Benzodiazepines
• Ethanol
• Indomethacin
• Nicotine
• Nifedipine
• Oral contraceptives
• Octreotide
• Theophylline

Equipment

Technetium-99m is a radioactive isotope of technetium which can be attached to iminodiacetic acid (IDA) compounds and their derivatives.  Current practice most commonly utilizes Tc-99m mebrofenin which is preferred due to its excellent extraction efficiency by the liver, which allows for diagnostic imaging of the biliary system in the presence of acute or chronic biliary disease.[10]

HBS acquisition requires a large field-of-view gamma camera together with a low-energy all-purpose collimator for imaging of the 140 keV photons of Tc-99m.[11]

Personnel

According to the Society of Nuclear Medicine Procedure Guideline for General Imaging, there are three required personnel types to calibrate equipment, administer radiopharmaceuticals, and interpret a nuclear study[12]:

1. A board-certified physician in either nuclear medicine (ABNM) or radiology (ABR), to include nuclear radiology
2. A medical physicist certified in “the appropriate subfield by the American Board of Science in Nuclear Medicine or by the American Board of Radiology”
3. A nuclear technologist certified “in Nuclear Medicine by the Nuclear Medicine Technology Certification Board”

Preparation

Patient optimization and preparation for hepatobiliary scintigraphy depends on the specific clinical question asked. For example, the preparation for the evaluation of cholecystitis is different than preparation for a biliary leak, which is different from the preparation for assessment of biliary atresia.

Acute Cholecystitis:

Patients must be fasting for at least 4 to 6 hours before radiotracer injection. Fat in food stimulates the secretion of endogenous cholecystokinin (CCK) by the duodenum, which causes gallbladder contraction and artificially absent filling of the gallbladder on the scan. Fasting for 4 to 6 hours generally allows for the complete passage of ingested contents, cessation of duodenal CCK secretion, and relaxation of the gallbladder.

On the other hand, fasting for more than 24 hours allows gallbladder time to resorb water from bile (a normal physiological process) which thickens the bile and often prevents radiotracer entry. This extended fast may lead to a false positive study (non-visualization of the gallbladder). In the fasting population, a cholecystokinin analog, sincalide, should be given prior to the study to contract and empty the bile content from the gallbladder. To accomplish this, intravenous sincalide is 0.02 micrograms/kilogram is administered over one hour. Tc-99m Mebrofenin should be injected at least 30 minutes after sincalide administration to allow adequate gallbladder relaxation.

As noted in the section on contraindications, opiates should be withheld for at least 6 hours if there is a concurrent concern for biliary obstruction.

Chronic Biliary Disease: 

As with acute cholecystitis, patients must be fasting for at least 4 to 6 hours prior to radiotracer injection, but no greater than 24 hours (though not typically a concern in the non-acute setting). 

As noted in the section on contraindications, opiates should be withheld for at least 6 hours since they may falsely depress the measured gallbladder ejection fraction. Other medications may also interfere with the gallbladder contraction, though are generally less of a concern.

Biliary Leak:

No special patient preparation is required to include no need to be fasting, avoid opiates or pretreat with CCK.

Biliary Obstruction:

As with cholecystitis, patients must be fasting for at least 4 to 6 hours prior to radiotracer injection, but no greater than 24 hours. 

As noted in the section on contraindications, opiates should be withheld for at least 6 hours since they increase the tone at the ampulla of Vater and therefore delay the flow of radiolabeled bile from the CBD into the duodenum. This pseudoobstruction may mimic a true mechanical obstruction, resulting in a false-positive result.

Biliary Atresia:

Phenobarbital-enhanced cholescintigraphy is used to differentiate neonatal jaundice and biliary atresia. Phenobarbital is a medication which induces hepatic enzymatic activity, bilirubin conjugation, and excretion. Given that the HBS radiotracers follow the same pathway as bilirubin, this preparation step helps reduce the risk of a false-positive result related to hepatic immaturity. The recommended dosing regimen is 5 mg/kg/day given for five days prior to the scan.[13]

Technique or Treatment

The first hour of the exam is fairly standard regardless of the indication. The patient is positioned supine on the gamma camera table. The radiotracer is rapidly infused, and anterior images are acquired at one-minute intervals. At one hour, left anterior oblique and right lateral views are often acquired to help definitively localize radiotracer activity in the common bile duct, gallbladder, and duodenum. On the left anterior oblique view, the anteriorly located gallbladder is seen to move laterally, differentiating it from posteriorly located common bile duct and duodenum which will be seen to move medially.[14] On the right lateral view, the anteriorly located gallbladder is seen to move to the right, differentiating it from posteriorly located common bile duct and duodenum which will be seen to move to the left.

After the first hour of the exam, various techniques are used depending on the results of the initial imaging as well as the clinical concern. 

Acute Cholecystitis:

The absence of radiotracer activity in the gallbladder signal at one hour is abnormal but not specific enough to diagnose acute cholecystitis. At this point, two options are available to assess definitively for the presence or absence of acute cholecystitis. The first is acquiring delayed imaging in 3+ hours (4+ from the administration of radiotracer). However, delayed images are suboptimal in the setting of acute cholecystitis when prompt diagnosis and intervention are preferred. A second, more expeditious option is the administration of a sub-analgesic dose of morphine which causes the sphincter of Oddi to contract and the ampulla of Vater to close; this diverts incoming bile to the gallbladder. In a normal patient with a patent cystic duct, filling of the gallbladder will be visible within 30 minutes after morphine administration. This technique allows the completion of the entire exam in 90 minutes. If there is continued non-visualization of the gallbladder after delayed images or morphine augmentation, this confirms the diagnosis of acute cholecystitis. If the gallbladder fills, then acute cholecystitis is excluded. Morphine administration in cholescintigraphy is approximately as accurate as delayed imaging with HBS having a sensitivity of 96% and specificity of 90%.[15]

It is worth noting that hepatobiliary scintigraphy is also a reflection of hepatic physiology. Therefore, in the setting of severe hepatic dysfunction and concurrent lack of significant excretion of the radiotracer into the bowel, further delayed imaging past the usual 4-hour protocol, out to as far as 24-hours, may be necessary to confirm cystic duct obstruction. 

Chronic gallbladder disease (aka chronic cholecystitis, functional gallbladder disease):

The hallmarks of chronic gallbladder disease (CGBD) manifest as delayed gallbladder filling or a depressed gallbladder ejection fraction (GBEF). In the setting of proper patient preparation and the absence of concurrent acute abdominal disease (i.e., pancreatitis, peptic ulcer disease, hepatitis) delayed the filling of the gallbladder (after 1-hour) is consistent with CGBD.[12] Since the majority of patients with CGBD demonstrate normal filling of the gallbladder within 1-hour, the disorder is more frequently identified by CCK-augmentation. CCK is administered as a 60-minute infusion (to minimize false-positives from supraphysiologic dosing), and images are acquired in one-minute frames for an additional 60 minutes.[16] Ejection fraction is calculated as a ratio of the difference of maximum and minimum activity/counts divided by the maximum gallbladder activity/counts, corrected for background activity. A GBEF of less than 38% is abnormal and indicative of CGBD in the appropriate clinical setting.

Biliary Leak:

A biliary leak is diagnosed when radiotracer is identified outside its normal biodistribution (e.g., outside the liver, biliary tree, and bowel). Most common locations are in the gallbladder fossa (post-cholecystectomy), in the right paracolic gutter or the perihepatic space. In the setting of brisk or large leaks, this may be present during the first hour of imaging. Delayed images may be obtained out to 24-hours to identify slow or small leaks. In indeterminate cases, alternative views (lateral or oblique) versus SPECT or SPECT-CT imaging may be helpful.

Biliary Obstruction/Atresia: 

If no radiotracer is seen in the bowel during the initial first hour of imaging, delayed biliary-to-bowel transit is present, which can be due to an obstructive process, though it may also be due to intercurrent illness, chronic cholecystitis, a normal variant in 20% of individuals, as well as seen in up to 50% of patients pre-treated with CCK. Delayed images out to 24-hours may be necessary to diagnose obstruction definitively. The degree of obstruction (low-grade/partial versus hi-grade/complete) can be inferred by the degree of delayed transit and amount of radiotracer reaching to the bowel. Biliary atresia, which is a congenital variant of complete biliary obstruction, is suggested scintigraphically when no radiotracer is seen in the bowel by 24-hours. This diagnosis is must then verified by an invasive procedure.

Complications

During a typical HBS, the patient will have exposure to 3 to 4 mSv of radiation which is roughly the amount of background radiation experienced in one year. For reference, a chest x-ray exposes the patient to 0.001 mSv of radiation while a computed tomography of the head requires 1 to 5 mSv.[17]

Clinical Significance

The utility of hepatobiliary scintigraphy is that the radiotracer follows the bilirubin pathway, taken up by hepatocytes, excreted into the bile ducts and passing into the gallbladder and duodenum; this allows for high sensitivity and specificity in the evaluation of biliary pathologies such as cholecystitis, obstruction or leak and to a lesser extent the assessment of hepatic function.

Enhancing Healthcare Team Outcomes

Nuclear imaging, like other imaging modalities, requires adherence to the 'as low as reasonably achievable' (ALARA) principle limiting patient radiation dose.[18] When the primary care provider/nurse practitioner orders a hepatobiliary scan, the nuclear radiologist should review the patient's previous imaging modalities, lab data, surgical history, and current medications. The nuclear medicine team must coordinate with the patient and the patient's medical providers including the nurse practitioner, physician assistant, and physician to ensure adequate patient preparation including appropriate time passage since the patient's most recent meal as well as risk assessment and possible cessation of medications that might interfere with biliary function.[2]