Hepato-biliary (HB) emergencies in an acute setting include a wide spectrum of conditions ranging from the inflammatory to the less frequent iatrogenic or oncological ones.1 Abdominal pain, together with jaundice, is the most common clinical presentation. Since the various HB emergencies require different therapeutic strategies (ie, medical, endoscopic, surgical, and/or percutaneous approaches), a prompt and correct diagnosis is of utmost importance. In this regard, abdominal ultrasound (US) examination, especially when performed at the emergency department, has gained a crucial role to get timely access to diagnostic information and predict the need for surgical intervention.2 However, in spite of its high sensitivity, US presents some limitations in terms of specificity, especially in some challenging settings (eg, emphysematous cholecystitis, perforation, or abscess); in such cases computed tomography (CT) or magnetic resonance imaging (MRI) are required.3

Nuclear medicine (NM) is not commonly considered as a first-line imaging modality in HB emergencies. Indeed, NM can provide valuable tools for the evaluation of several inflammatory and noninflammatory conditions related to the HB system. As concerns the applications of single-photon emitting tracers, hepato-biliary scintigraphy (HBS) with iminodiacetic-acid (HIDA) has been successfully applied for the examination of patients with right upper quadrant pain, especially in the case of acute or chronic cholecystitis or biliary leak.4 White blood cell (WBC) scintigraphy, especially when performed by single photon computed tomography (SPECT/CT), has been employed for the diagnosis and localization of abdominal infective processes.5 Positron emission computed tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG), carried out by hybrid imaging with CT (PET/CT) or MRI (PET/MRI), has a well-established role both in oncological and non-oncological field, but its potential in HB emergencies has not been fully investigated yet.6 The aim of this review is to provide an update on the applications of NM in patients presenting HB disease in the acute setting, with a particular emphasis on the added value of hybrid imaging.

Biliary inflammatory disease, involving the biliary tree, cholecystitis or pancreas, represents a common cause of HB emergency.1 In particular, acute inflammation of the gallbladder, determined by cholelithiasis and obstruction of the cystic duct by gallstones (ie, acute calculous cholecystitis [AC]) can require urgent laparoscopic cholecystectomy as treatment of choice.7 It has to be underlined that prolonged inflammation of the gallbladder can entail the development of hemorrhage and necrosis areas; in addition, biliary stasis due to obstruction may foster bacteria proliferation and infection, therefore leading to the onset of pericholecystic abscess. Acalculous cholecystitis (ACC) is an uncommon and potentially severe cause of HB emergency. Several clinico-pathological conditions (ie, diabetes mellitus, malignant disease, abdominal vasculitis, congestive heart failure, cholesterol embolization, shock, and cardiac arrest) have been associated with ACC, whose pathogenesis is complex and multifactorial.8 Since patients affected by ACC are often poor surgical candidates due to their severely debilitating conditions, medical therapy is generally preferred over other options. Acute cholangitis, an inflammation of the biliary tree, can be determined by obstruction of the common bile duct, followed by bacteria proliferation. In this regard, gallstones and malignancies are reported as the main causes of obstruction.9 Clinical management of cholangitis is not always easy, due to the variability of clinical presentation ranging from few/ no symptoms to debilitation, fever and septic status, therefore its mortality is strictly dependent on early diagnosis and treatment. However, it has to be underlined that the clinical management of inflammatory HB disease (ie, AC, ACC, cholangitis) is mainly based on the algorithms defined by the Tokyo Guidelines 2018 (TG18) that have been adopted worldwide and clearly lay out all the diagnostic criteria to score the severity grade of the aforementioned conditions and also define the most appropriate therapeutic strategies.9 The adoption of TG18 resulted in reduced overall mortality, length of hospital stay, conversion rates to open surgery, and medical costs.10

Acute pancreatitis (AP), whose etiology is more often due to a gallstone impacting the distal common bile-pancreatic duct, is a leading cause of hospitalization in Western countries: pancreatic duct obstruction and consequent pancreatic activity hyperstimulation leads to auto-digestion of the gland and inflammation.11 Of note, this condition has a broad range of manifestations: less severe inflammation may be successfully managed with conservative therapy, while complicated disease presents high mortality, especially in the case of necrotizing AP.12

Pyogenic liver abscess (PLA) is a severe, life-threatening HB infective condition. PLA more often arises as a complication of biliary tree disease or in patients affected by abdominal infections, nevertheless it can also occur in subjects without clear risk factors and, in such cases, is defined as “cryptogenic PLA”.13 Especially in patients without predisposing factors, diagnosis may be challenging due to the nonspecific clinical manifestations (abdominal pain, fever, nausea, and vomiting). Percutaneous drainage and antibiotics represent an up-front therapy for PLA, with a meaningful impact on patients’ outcome. From a microbiological point of view, escherichia coli, enterobacteriaceae, anaerobes, and other members of the gastrointestinal flora, are frequently identified as etiological agents.14

Beside inflammatory and infective HB emergencies, iatrogenic non-traumatic injuries of the biliary tree are worthy of mention. Biliary injuries during cholecystectomy are relatively infrequent. Nevertheless, when iatrogenic biliary damages are not promptly identified in the immediate postsurgical period, patients get back to the hospital complaining vomiting, nausea, abdominal discomfort and other nonspecific symptoms mainly due to biliary leak, sometimes determining the formation of a well-circumscribed, extra-biliary collection of bile (ie, bilioma). Accurate clinical examination and an in-depth imaging are mandatory to identify the damaged biliary duct, drain the biliary liquid in the abdominal cavity and then aid surgeon in the intervention through laparoscopic or open-abdomen access.15

A further consideration has to be made about malignancies. Both primary and secondary hepatic tumors rarely can be considered a HB emergency in themselves. However, as previously mentioned, tumor growth can determine a “mass effect” with consequent biliary tree obstruction. In particular, malignant biliary obstruction has been reported in cases of adenocarcinoma or neuroendocrine tumors of the pancreatic head, periampullary neoplasms, cholangiocarcinoma, and metastatic lymphadenopathy in the hepatoduodenal ligament.16, 17, 18 Other conditions, such as tumor-associated bleeding or spontaneous rupture of massive hepatocellular carcinoma, are extremely rare and life-threatening conditions.19

Aside from clinical examination and laboratory investigations, these last often showing nonspecific alterations (eg, increased hepatic enzymes, white blood cells, neutrophils, and C-reactive protein levels), abdominal US represents the first-line imaging modality in patients accessing to emergency department with symptoms/signs suggestive of HB disease.10 In this regard, the additional value of color or power Doppler, although some preliminary reports suggest its potential usefulness to assess gallbladder adhesions to predict the grade of surgical difficulty, has not been sufficiently investigated yet.10 Although US is a simple, relatively cheap, and effective diagnostic modality, its accuracy may be hampered by several factors: strong subjectivity, differences in diagnostic criteria, and abdominal intestinal gas interference.20 In case of US equivocal findings, the execution of CT or MRI, specifically magnetic resonance cholangiopancreatography (MRCP), is recommended for the diagnosis of AC.

It has to be underlined that US has a limited role for the diagnosis of acute cholangitis. Although US can be helpful for the visualization of the abnormal dilatation of the biliary duct, this imaging modality has, in fact, good specificity but low sensitivity.21 In spite of these limitations, US is commonly carried out as the first-line examination in patients with suspicion of acute cholangitis due to its lack of invasiveness and great availability. CT is not hampered by intestinal gas, can accurately image biliary duct dilatation, identifies residual choledocholithiasis after cholecystectomy and is capable of discriminating between lithiasic and non-lithiasic obstruction. Nevertheless, CT has limited sensitivity for the detection of duct stones with a low amount of calcium, with a detection rate ranging 25%-90%.22 MRCP provides an excellent quality imaging of the entire biliary tree and is characterized by superior diagnostic performance respect to CT for the visualization of small calculi, therefore representing a valuable alternative to the more invasive endoscopic retrograde cholangiopancreatography (ERCP).23 Nevertheless, due to its limited accessibility, MRCP is recommended for the diagnosis of acute cholangitis only when diagnosis cannot be obtained with abdominal US and/or CT. MRCP covers also a fundamental role in the clinical assessment of AP, thanks to its capability to accurately depict both parenchymal and pancreatic duct abnormalities; in this regard, it provides essential information for the differentiation between interstitial edematous and necrotizing pancreatitis.24

The discovery of HIDA derives from a scientific failure subsequently reconsidered from a different point of view and then turned into a success. As a matter of fact, during some investigations to synthesize a radiopharmaceutical adequate for cardiac imaging, it was noted that 99mTc-labeled lidocaine was not suitable for the cardiac purpose but showed a clearance through the HB system.25 With a chemical modification of the lidocaine molecule, HIDA was obtained and, as early as in 1986, it was approved for HB imaging by the Food and Drug Administration (FDA). Although other molecules with similar characteristics were developed (ie, PIPIDA, BIDA, EIDA, DIDA, DISIDA, etc.), HIDA still remains the most popular imaging agent employed for HBS. After intravenous (i.v.) administration, 99mTc-HIDA binds to albumin, from which it dissociates within the perisinusoidal space. Subsequently, the radiopharmaceutical is taken up by hepatocytes through receptor-mediated endocytosis, then follows the same metabolic pathway as bilirubin.26

From a technical point of view, patients are instructed to fast 3 to 4 hours before 99mTc-HIDA injection to favor gallbladder relaxation. Patient is positioned supine on a table, then 99mTc-HIDA is rapidly i.v. administered, and a dynamic scan is started immediately after injection. The scan is composed of a first phase of 60 one-second frames, followed by a second phase by 60 one-minute frames. After 1 hour, static images in anterior, oblique and lateral projections are acquired to discriminate common bile duct, gallbladder, and duodenum. After the first hour of examination, HBS can be prolonged on the basis of the specific clinical question.27 As specifically concerns AC diagnosis, the absence of gallbladder visualization after 1 hour is strongly suggestive for AC diagnosis, but not specific or sensitive enough. Therefore, in order to increase diagnostic accuracy, delayed static images after 3 or 4 hours are recommended. As an alternative to the prolonged acquisition, a sub-analgesic dose of morphine can be administered: in physiological conditions a filling of gallbladder occurs within 30 minutes, while the continued lack of gallbladder signal up to 90 minutes from morphine administration can confirm AC diagnosis. Although the gallbladder nonvisualization is the specific diagnostic criterion for AC at HBS, the “hot-rim” sign has been reported as the hallmark of a particularly severe condition and is determined by the image contrast between the photopenic area in the gallbladder and the inflammatory reaction of the adjacent hepatic parenchyma.28

It is still debated which is the role of 99mTc-HIDA HBS with respect to abdominal US in the initial framework of AC. In this regard, Kaoutzanis et al.29 carried out an interesting retrospective analysis on 406 patients who accessed the emergency department with acute upper abdominal pain. Three groups of patients were identified: subjects who underwent only US (n = 132), those who received only HBS (n = 46) and patients who underwent both modalities (n = 228). The authors found that the sensitivities of US alone, HBS alone, and US plus HBS for AC diagnosis were 73.3%, 91.7%, and 97.7%, respectively. Similar results were reported by Rodriguez et al. 30 who assessed the value of HBS with 99mTc-HIDA as confirmatory diagnostic test in patients with a preadmission US diagnosis of AC: US and 99mTc-HIDA had a sensitivity of 26% and 87% and showed a specificity of 80% and 79%, respectively. Therefore, the authors proposed HBS to confirm AC diagnosis and improve outcome in patients with comorbidities and at high-risk for laparoscopic or open-abdomen surgery, particularly in the case of acalculous cholecystitis,31 as schematized in Figure 1. 99mTc-HIDA HBS has been employed for the imaging of biliary obstruction and congenital biliary atresia, both characterized by delayed or absent (in the case of atresia) tracer transit in the bowel. In Figure 2 is reported a case of a woman with persistent symptoms of acute cholecystitis, but with negative findings at conventional imaging. 99mTc-HIDA demonstrated the absence of tracer elimination from the coledocus in the first 1h acquisition. After the subsequent administration of fat food (cheese and milk), scintigraphic images demonstrated the release of the tracer in the intestinal loop. The scintigraphic findings were compatible with sphincter of Oddi dysfunction (SOD).

99mTc-HIDA HBS can be applied for the diagnosis of biliary leak, in such a case diagnosis is based on the evidence of tracer progressive accumulation outside its physiological distribution (biliary tree, liver, bowel), most commonly in the perihepatic space and the gallbladder fossa. Notably, while more relevant leak can be visualized as early as at 1 h p.i., delayed images up to 24 hours may be required to identify small or slow leak. In this regard, it has been reported that the use of hybrid SPECT/CT imaging can improve diagnostic accuracy, providing a precise localization of the leak site.32

Scintigraphy with autologous white blood cell (WBC scan), labeled with 111In or 99mTc-HMPAO, has been widely used in clinical practice for the diagnosis and location of infective and inflammatory processes, providing valuable information, especially when performed by hybrid SPECT/CT imaging.33 However, it has to be underlined that the detection of hepato-splenic abscesses by WBC scan is strongly hampered by the physiological cell accumulation within liver and spleen.34,35 In such cases, the combined use of WBC sean with 99mTc-sulfur colloid scintigraphy has been reported to improve diagnostic accuracy: in 90 patients with suspected upper abdomen abscesses, Datz et al.36 carried out WBS scan with 111In-labeled leukocytes immediately followed by hepato-splenic scintigraphy with 99mTc-sulfur colloids. In such cases, discrepancies of pattern uptake between the two imaging modalities (WBS scan vs hepato-splenic scintigraphy) were reported to be essential to confirm diagnosis in 57% of cases. However, it has to be underlined that, in consideration of its low diagnostic accuracy and the overall radiation burden to patients, WBC scan is not commonly considered in the diagnostic assessment of PLA.

The role of WBC scan in the diagnosis of pancreatitis is another debated issue. First clinical experiences with 111In-labeled WBC have shown a low specificity for the differential diagnosis between abscess formation and fat necrosis in the peripancreatic tissue. However, WBC scan's accuracy in pancreatitis seems to be strongly influenced by the type of labeling, since planar images and SPECT at 1 and 3 hours after i.v. administration of autologous 99mTc-HMPAO-labeled granulocytes showed superior diagnostic performance with respect to static images at 3-4 and 24 hours after the injection of 111In-labeled cells.37 In this regard, López et al.38 reported the usefulness of 99mTc-HMPAO WBC scan to detect pancreatic leukocyte infiltration in patients with AP. In the cited paper, a prospective cohort of 84 with AP was submitted to 99mTc-HMPAO WBC scan. Labeled-cell uptake in pancreas was assessed on a 0-3 scale and WBC scan impact on the prediction of pancreatic necrosis (PN) was evaluated, also in comparison with serum C-reactive protein (CRP) levels and ce-CT findings. WBC scan outperformed both CRP levels and ce-CT for PN prediction, since subjects with 2-3 score on WBC images had a 71-time higher risk for PN than those with score 0-1. However, in spite of these preliminary encouraging results, the applications of WBC in pancreatitis remained limited to anecdotic observations, most probably due to the time-consuming procedure required for WBC labeling with the biological risks related to blood manipulation. In this context, PET/CT with 18F-FDG-labeled autologous leukocytes could carve out a role in the future for the assessment of AP, as suggested by a preliminary work on 41 patients by Bhattacharya et al.39 Indeed, 18F-FDG-labeled autologous leukocytes PET/CT combines the specificity of conventional WBC scan with the high spatial resolution of PET/CT and may therefore guarantee early and specific detection of pancreatic infection underlying AP. Nevertheless, further consistent literature evidences are needed to see this imaging method break into daily clinical practice.

18F-FDG PET/CT or PET/MRI is not routinely performed for imaging acute HB diseases. Nevertheless, the wide-ranging use of these hybrid techniques in the diagnostic algorithm of several oncologic and inflammatory/septic diseases led to the detection of some incidental findings, including a few HB diseases, in acute settings. The first evidence of AC on 18F-FDG PET/CT derives from case reports, describing patients mainly performing the scan for fever of unknown origin (FUO). Interestingly, AC is reported to present with a rim-sign, consisting in an increased radiotracer uptake in the wall of the gallbladder, surrounding a “cold” area corresponding to the lumen40, 41, 42 as shown in Figure 3. This characteristic presentation might reflect the uptake of 18F-FDG by activated inflammatory cells in the gallbladder wall. Of note, available literature mainly describes patients without signs of AC at conventional imaging. Therefore, 18F-FDG PET might play a role to detect occult AC at conventional imaging, particularly in patients with FUO. Moreover, the evidence of the rim-sign at 18F-FDG PET/CT may aid the NM physician in the differential diagnosis between AC and gallbladder cancer, with the latter usually presenting as a focal uptake involving also the lumen, without contextual photopenic areas.43 In a recent paper by Li et al.,44 the authors propose a diagnostic model, based on both metabolic parameters extracted by 18F-FDG PET/CT and clinical variables (including presence of fever, cholecystolithiasis, and carcinoembryonic antigen assay > 5 ng/mL), able to discriminate AC from gallbladder cancer. Of note, the combined diagnostic model presented an area under the curve (AUC) = 0.89, significantly higher than that obtained by clinical variables alone. Nevertheless, despite these promising results, the current role of 18F-FDG PET in the characterization of AC is still limited in daily clinical practice.

Obstructive jaundice (OJ) is another clinical presentation of HB disease, with acute onset. OJ is due to the complete or incomplete obstruction of the bile outflow and is usually rapidly progressing with the potential to become a life-threatening condition.45 Several pathological conditions may lead to OJ, including ab-extrinsic malignant compression of the bile ducts, or ab-intrinsic obstruction due to bile duct stones, or pancreato-biliary inflammation. Conventional imaging (including US, MRI, and cholangiopancreaticography [ERCP]) is of utmost relevance to detect the underlying causing disease, whereas in this context, 18F-FDG PET is not routinely performed. Wang et al.,46 explored the added value of 18F-FDG PET/CT to conventional imaging in the characterization of the primary cause of OJ in a cohort of 85 patients. 18F-FDG PET/CT improved sensitivity (75.8% vs 95.5%; p < 0.05), and overall accuracy (74.1% vs 87.1%; p < 0.05) of conventional imaging in the study population, thus the authors conclude that it should be performed to obtain a more accurate characterization of the OJ etiology. This result is consistent with a few case reports, in which 18F-FDG PET/CT detected a malignancy determining OJ.47 Of note, in case of a suspected neuroendocrine tumor NET) (i.e. cephalo-pancreatic or duodenal NET) also PET/CT with somatostatin analogues (SSA) radiolabelled with 68Ga (68Ga-DOTA-SSA PET/CT) should be considered and performed. Nevertheless, CI is usually able to discriminate ab-extrinsic vs ab-intrinsic cause of OJ and PET/CT could eventually be used in case of inconclusive findings, although larger cohort studies are needed to prove its real potential in this setting.

PLA can represent another occasional finding in 18F-FDG PET/CT carried out in oncological patients, as shown in Figure 4. In this regard, Tan et al.48 reviewed all the PET/CT scans performed over a 5-year period in their institution and retrieved all the cases showing focal 18F-FDG incorporation in the liver with available histology: although the majority of lesions were attributable to malignancies, increased tracer uptake was also found in several non-neoplastic lesions such as cryptococcosis, abscesses, and secondary inflammation from cholecystitis. PET/CT was successfully employed in complex autoinflammatory disorders frequently manifesting as recurrent abdominal pain and fever, particularly in the case of aseptic abscesses, in which PET/CT showed higher sensitivity for patients’ monitoring and follow-up than CT.49

Finally, one of the most common complications of laparoscopic cholecystectomy is the risk of gallbladder perforation. This eventuality may result in the scattering of bile stones into the abdomen that may be difficult to retrieve by the surgeon.50 Despite spilled bile stones may remain silent within the abdominal cavity even for years, they can become infected and produce abscesses, and peritonitis, determining an acute emergency. The inflammatory process surrounding spilled bile stones can be detected by 18F-FDG PET/CT, which may guide the surgeon to find and remove them more easily. A case report by Gorospe et al.51 was the first evidence of the use of 18F-FDG PET/CT for this indication, followed by a few more cases, confirming its potential utility.52

Data about the role of PET/MR in acute disease are very scarce in literature. Indeed, few clinical cases have been described about the role of PET/MR in acute inflammatory processes, such as encephalitis or myocarditis53,54 by using different radiopharmaceutical agents. However, by considering the advantages of MRI, such as high contrast resolution and the opportunity to assess the biliary tree without using a contrast agent, a hybrid PET/MRI scanner or coregistration of PET and MRI images would be useful for completing the management of patients with an acute HB disease. Primary sclerosing cholangitis, Caroli disease and cholangiocarcinoma are hepatobiliary diseases often associated with an acute emergency. Primary sclerosing cholangitis, commonly seen with inflammatory bowel disease, such as ulcerative rectocolitis, is correlated with an increased risk of premalignant and malignant lesions, such as cholangiocarcinoma. In this setting, 18F-FDG PET/MR can be useful to assess the presence of premalignant/malignant involvement, as illustrated in Figure 5.

Caroli disease is a rare congenital liver disease characterized by nonobstructive cystic dilatations of the intrahepatic and rarely extrahepatic bile ducts. The development of intrahepatic/extrahepatic carcinoma has been described with variable incidence.55 Due to its intrinsic contrast resolution and due to the association with FDG, PET/MR can help to detect the presence of an intrahepatic/extrahepatic cancer that can significantly worsen the prognosis of patients affected by Caroli disease. In Figure 6 is reported an example of a patent with a Caroli disease associated with a malignant transformation in cholangiocarcinoma.

Based on the above mentioned information, PET/MR with 18F-FDG or other tracers can be useful to evaluate the potential transformation in malignant lesions in patients with pre-existing congenital or autoimmune hepatobiliary disease. Indeed, extrahepatic tumors, such as cholangiocarcinoma, pancreatic adenocarcinoma, and ampullary carcinoma can present with painless jaundice, pruritus and weight loss that should be made in differential diagnosis with the other reasons of biliary signs/symptoms. However, in an hypothetical diagnostic flow-chart of patients with an acute hepatobiliary disease, PET/MR would be considered, but postponing it after solving the emergency symptoms.

In the future some additional efforts should be done for establishing the role of NM procedures in the management of patients with acute biliary disease. The development of more rapid scanners, such as 3-D ring CZT SPECT/CT, LAFOV and digital PET/CT, and also the introduction of new radiopharmaceutical agents, such as FAPI would change the diagnostic strategies to employ in this setting of disease. Indeed, CZT SPECT/CT, LAFOV, and digital PET/CT scanners have a short acquisition time, thus accelerating the imaging procedures, mainly in case of acute disease, and therefore the final imaging assessment.56 As for the radiopharmaceutical agents, 18F-FDG-labeled autologous leukocytes PET/CT could see a rising use for the assessment of infections, in particular those related to AP. Moreover, Fibroblast Activation Protein Inhibitor-based agents could be used to evaluate inflammatory disease because fibroblast activation protein has a profibrogenic role in hepatobiliary injury.57