Introduction

Cholecystokinin (CCK), formerly referred to as pancreozymins, is another hormone-like secretin used in the pancreas's stimulation. Secretin mainly stimulates the secretion of pancreatic juice, which contains pancreatic enzymes and acts on the gallbladder, which can assess gallbladder function.[1] CCK increases pancreatic enzyme output and causes gallbladder contraction.[1] Therefore, the CCK test can help to diagnose biliary tract diseases.

Cholecystokinin-cholescintigraphy (CCK-HIDA) is the gold standard test for evaluating patients for obstructive cholecystitis or biliary dyskinesia. The finding of an abnormal gallbladder ejection fraction (GBEF) could signal the presence of an array of disease entities, including biliary dyskinesia, chronic or acute cholecystitis, and bile sludging. The HIDA may also demonstrate a filling defect, which represents a likely stone lodged in the cystic duct. Cholecystectomy is the recommended approach for those with abnormal GBEF and abdominal pain.[2] GBEF is calculated as the flow of radioactive tracer that is ejected from the gallbladder. A GBEF of less than 35% is considered abnormal. Patients considered for CCK-HIDA are those presenting with functional biliary pain based on the Rome III criteria. Those who present with atypical pain may not need a HIDA as the presentation may be from other pathology.[2]

Procedures

Preparation for the cholecystokinin test includes:

• Patients are required to be nil per os for up to 4 hours before the CCK test; this is to avoid endogenous secretion of CCK, which can cause gallbladder contraction and, in turn, inhibit the absorption of the radiotracer, which may lead to false-positive test results. During the period of prolonged fasting, bile in the gallbladder becomes too vicious and turns into sludge, which prevents the radiotracer from entering the gallbladder.[3] CCK is used to dislodge this sludge before the CCK-HIDA scan to avoid false positives.
• The clinician should make a note of the other medications taken by the patient.
• Intravenous access: Before gaining intravenous access, the patient receives instructions regarding the procedure of the test. After this counseling session, the CCK will be injected through the vein, and the imaging will be done over the patient's abdomen. During that time, the patient should remain still.
• Sincalide is the synthetically prepared C-terminal octapeptide of cholecystokinin commonly used in nuclear medicine hepatobiliary studies. Its purpose is to reduce the size of the gallbladder by emptying it for better visualization.[4] Crick and his colleagues designed a method used to prepare for CCK testing. This method included assaying CCK from pig intestine after infusing it with 1.7 units per kilogram of secretin for each dose.[1]
• At present, 40 ng/kg/hr of CCK infusion for five minutes after using a secretin test dose (intravenous bolus of 0.2 mcg/kg).[5]
• Pain medications like morphine may also be used during the procedure.

Indications

Abdominal pain is a frequent complaint and the reason many people present to emergency departments or clinics. Right upper quadrant pain is commonly associated with biliary diseases. Qualitative cholescintigraphy can evaluate gall bladder emptying. Clinicians often employ CCK cholescintigraphy/HIDA when biliary pain presents with a RUQ ultrasound showing obvious gallstones or in a normal-appearing ultrasound in the setting of classic physical exam findings associated with biliary disease.[6] Chronic cholecystitis is clinically diagnosed by poor gallbladder contractility due to prolonged inflammation. HIDA helps diagnose not only the delayed emptying but also the impaired squeeze of the gallbladder (GB) musculature.[2] When there is high clinical suspicion of a calculus obstruction, the HIDA scan without CCK helps demonstrate GB filling but not squeeze.

Potential Diagnosis

CCK-HIDA scan is used to diagnose or rule out the following potential diagnoses:

• Gallbladder dyskinesia
• Biliary dyskinesia
• Acute acalculous cholecystitis  
• Acute calculous cholecystitis
• Chronic cholecystitis
• Functional biliary disease
• Prolonged fasting [3]

Normal and Critical Findings

A GBEF of less than 35% after a 3-minute infusion is considered abnormal. However, the symptoms of a few patients did not resolve after cholecystectomy. Previous studies show that those with such false positive GBEF received unnecessary cholecystectomy.[7] All these findings confirm that the symptoms can be secondary to a non-biliary cause and that this procedure could yield definite false positives.[7]

Various researchers, over the years, studied different doses and infusion times for the CCK test. The challenge of using this important test is to find the correct combination of dose and time, which provides the least variability.  Following more robust studies, the Hepatobiliary Practice Guideline of the Society of Nuclear Medicine recommends that a 60-minute infusion of CCK  at the rate of 0.02 mcg/kg be considered the standard method where GBEF of more than 38% is normal.[7] Chronic cholecystitis is the diagnosis when the GBEF is 6%, with the infusion of 0.01 mcg/kg of CCK over 3 minutes. There is significant variability in the GBEF when using this technique since different doses and infusion rates can yield false-positive results. An abnormal response to CCK stimulation by the sphincter of Oddi is also observable in patients with irritable bowel syndrome.

Interfering Factors

Food intake is the major factor that interferes with this test. False positives arise based on the contracted state of the gallbladder in the presence of food.[3] Of note, patients who have been kept nothing by mouth for an extended period may have thicker bile, often referred to as sludge, which may affect the test results, leading to false positives.

Complications

The test is usually safe; however, the patients undergoing the test should receive information regarding the necessary precautions.

• Pain: If using a HIDA scan with CCK, patients should be warned that the test will likely bring on very similar pain to what they felt previously, especially in the setting of calculus. The test may be very painful. 
• Allergy
• Radiation exposure
• Bruising/thrombophlebitis at the site of the IV infusion 

Patient Safety and Education

Patients with abdominal pain and, generally, an ultrasound that shows gallstones often receive a referral to undergo a CCK-HIDA scan. The patients must understand that this test will determine the functionality of their gall bladder. An abnormal GBEF of less than 35% confirms that a diagnosis of biliary dyskinesia, or with a filling defect, an obstructed cystic duct is present, and cholecystectomy may relieve their symptoms. It is a good prediction for the successful resolution of symptoms following cholecystectomy. This procedure is tolerated well by the patients.[8] As the radioactive tracer may take some days to exit from the bloodstream via urine or stool, the patients should increase the intake of water for a short period post-procedure.

Clinical Significance

Previously, clinicians used fatty meals to ascertain the status of gallbladder function; however, it had its limitations and did not give the same evidence as a 60-minute infusion of CCK.[7] CCK-infusion method is substantiated and is better tolerated by patients, especially those with severe abdominal pain. The CCK-cholescintigraphy test is useful in predicting the efficacy of cholecystectomy, and it is the gold standard for assessing gallbladder emptying and function.[6] Effectively, the CCK-HIDA/scintigraphy can rule out functional obstruction of the cystic duct; this may be from biliary dyskinesia (failure of gallbladder contraction) or acalculous cholecystitis (sludging of bile). Patients with abnormal GBEF on a CCK test tend to have a complete resolution of their symptoms following cholecystectomy.[8] Despite all the guidelines and research, the actual value of a GBEF in a diseased patient is not clear. All values used to define abnormal GBEF are based on healthy individuals.[2] Therefore, it is the responsibility of clinicians to consider the larger picture while diagnosing biliary or gallbladder dyskinesia.