Hepatobiliary-specific Contrast Agents Research Articles

Magnetic Resonance Cholangiography Diagnosing Post-cholecystectomy Biliary Injuries.

This study aimed to determine the diagnostic performance of contrasted magnetic resonance cholangiography for detecting bile duct lesions following cholecystectomy. A retrospective case series study was conducted that included patients over 18 years of age with suspected bile duct injury after cholecystectomy, who underwent contrasted magnetic resonance cholangiography, and who also had endoscopic retrograde cholangiopancreatography, surgery, or subsequent clinical follow-up. The images were interpreted by two radiologists who assigned the type of lesion according to the Strasberg classification. Qualitative variables were represented by frequencies and proportions, while quantitative variables were described using measures of central tendency and dispersion. Sensitivity, specificity, and predictive values were assessed, along with interobserver variability, using the kappa index. We included 20 patients with a median age of 51.5 years (interquartile range: 35), and 14 (70%) were women. In all 20 patients, lesions were identified on magnetic resonance cholangiography, of which 19 were confirmed with the gold standard for a positive predictive value of 100% (hepatobiliary-specific contrast agents) and 92% (extracellular contrast). The most frequent lesions were Strasberg E2 and E4 in five patients each. The kappa index was 1 in determining the presence or absence of bile duct injury and 0.9 in the Strasberg classification. Contrasted magnetic resonance cholangiography is a method with high positive predictive value and almost perfect interobserver agreement for diagnosing bile duct lesions after cholecystectomy.

Association Between Gadoxetic Acid-Enhanced Magnetic Resonance Imaging, Organic Anion Transporters, and Farnesoid X Receptor in Benign Focal Liver Lesions.

The organic anion uptake and efflux transporters [organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and multidrug resistance-associated protein (MRP)2 and MRP3] that mediate the transport of the hepatobiliary-specific contrast agent gadoxetate (Gd-EOB-DTPA) are direct or indirect targets of the farnesoid X receptor (FXR), a key regulator of bile acid and lipid homeostasis. In benign liver tumors, FXR expression and activation is not yet characterized. We investigated the expression and activation of FXR and its targets in hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH) and their correlation with Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI). Gd-EOB-DTPA MRI patterns were assessed by an expert radiologist. The intensity of the lesions on the hepatobiliary phase was correlated to mRNA expression levels of OATP1B1, OATP1B3, MRP2, MRP3, FXR, and small heterodimer partner (SHP) in fresh surgical specimens of patients with FNH or HCA subtypes. Normal and tumor sample pairs of 43 HCA and 14 FNH were included. All FNH (14/14) were hyperintense. Of the 34 HCA with available Gd-EOB-DTPA-enhanced MRI, 6 were hyperintense and 28 HCA were hypointense. OATP1B3 was downregulated in the hypointense tumors compared with normal surrounding liver tissue (2.77±3.59 vs. 12.9±15.6, P < 0.001). A significant positive correlation between FXR expression and activation and OATP1B3 expression level was found in the HCA cohort. SHP showed a trend toward downregulation in hypointense HCA. In conclusion, this study suggests that the MRI relative signal in HCA may reflect expression level and/or activity of SHP and FXR. Moreover, our data confirms the pivotal role of OATP1B3 in Gd-EOB-DTPA uptake in HCA. SIGNIFICANCE STATEMENT: FXR represents a valuable target for the treatment of liver disease and metabolic syndrome. Currently, two molecules, ursodeoxycholate and obeticholate, are approved for the treatment of primary biliary cirrhosis and cholestasis, with several compounds in clinical trials for the treatment of metabolic dysfunction-associated fatty liver disease. Because FXR expression and activation is associated with gadoxetate accumulation in HCA, an atypical gadoxetate-enhanced MRI pattern might arise in patients under FXR-targeted therapy, thereby complicating the differential diagnosis.

Subtyping of hepatocellular adenomas using Gd-EOB-DTPA: a qualitative and quantitative analysis.

The goal of medical imaging is not only to identify the entity "hepatocellular adenoma," but to detect typical magnetic resonance (MR) patterns of the subtypes so that lesions with a higher malignant transformation rate could be differentiated from those that should just be controlled. To evaluate the differentiation between subtypes of hepatocellular adenomas using hepatobiliary specific contrast agent (Gd-EOB-DTPA) in MR imaging. A total of 11 patients with 39 lesions with histologically proven hepatocellular adenomas were evaluated. Of the, 34 were inflammatory hepatocellular adenomas (IHCA) and 5 were HNF1α adenomas. No β-catenin-mutated adenoma was found. In all patients, a standard protocol considering the guidelines of the international consensus conference of Gd-EOB-DTPA was performed in a 1.5-T scanner. Besides a qualitative analysis of all sequences, we measured the quantitative signal intensity (SI) ratio in all examinations. Qualitative analysis showed that best sequences for differentiation of HNF1α adenomas from IHCA were T1-weighted (T1W) precontrast (P = 0.03) and portalvenous phase (P < 0.0001) as well as arterial phase (P = 0.002). All adenomas were hypointense in hepatobiliary phase (15 min). The quantitative analyses of the SI ratio and of lesion-to-liver contrast (LLC) ratio show statistically significant differences in T1W precontrast (SI: P = 0.035; LLC: P = 0.049) and portalvenous phase (SI: P = 0.002; LLC: P = 0.002). Subtyping of hepatocellular adenomas using Gd-EOB-DTPA is possible due to qualitative and quantitative analyses regarding T1W precontrast and portalvenous phase. In addition, the SI ratio and liver-to-lesion contrast ratio in the arterial phase gave additional qualitative information for differentiation.

Application of Diffusion-Weighted Imaging and Hepatobiliary-Specific Contrast Agent Gd-EOB-DTPA in the Diagnosis and Differential Diagnosis of Focal Liver Lesions

There are many types of focal liver lesions (FLL) presenting different lesion signs and their diagnosis and differential diagnosis are relatively difficult. It is of great clinical significance to accurately detect, classify and characterize focal liver lesions as soon as possible. Diffusion-weighted imaging (DWI) provides information on liver cell density, microstructure, and microcirculation perfusion. Gadolinium-ethoxibenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is a hepatobiliary-specific contrast agent. Gd-EOB-DTPA-enhanced MRI examination of liver provides information on the blood perfusion of lesions and specific information on the uptake function of normal liver cells. The combined application of the two can significantly improve the sensitivity and diagnostic accuracy in the detection of FLL. Herein, we reviewed the research findings on the application of DWI and Gd-EOB-DTPA in FLL diagnosis in order to provide reference for further clinical application. Most of the existing studies only made comparison and discussion of the DWI image quality of different b values and their fitted apparent diffusion coefficient (ADC) values before and after Gd-EOB-DTPA enhancement, and the reported findings are not only varied, but also inconsistent. Whether Gd-EOB-DTPA will affect DWI images is still been debated. Future research should focus on quantitative comparison, discussion and verification of the enhancement effect after injection of Gd-EOB-DTPA, as well as the changes in the ADC value corresponding to different b values before and after enhancement, in order to provide more objective and consistent research results for clinical application.

Pharmacoeconomic Study on the Application of Magnetic Resonance Imaging with Gadoxetic Acid in Addition to Contrast-Enhanced Computed Tomography in Diagnosis of Hepatocellular Carcinoma

Objective: to evaluate pharmacoeconomic advantages of the application of magnetic resonance imaging (MRI) with hepatobiliary-specific contrast agent – gadoxetic acid in addition to contrast-enhanced computed tomography (CT) in the diagnosis of hepatocellular carcinoma (HCC).Material and methods. We performed the modeling and obtained the results of the pharmacoeconomic study: effectiveness analysis, cost analysis, and cost-effectiveness analysis. The cost analysis included only direct medical costs (the cost of contrast-enhanced CT, gadolinium-based contrast agent (GBCA) for MRI, and therapy per a patient with verified HCC diagnosis after diagnostic procedures). The financing was performed from the Compulsary Health Insurance Fund. The calculations were made per 1 patient.Results. The effectiveness analysis showed that the diagnostic scheme CT + MRI with gadoxetic acid was the most effective complex for the diagnosis of HCC because its application provided 50% of patients with 5-year overall survival (4.8 years), which was significantly higher than in patients who were diagnosed HCC with CT + MRI with extracellular GBCA (2.3 years) or CT (3.7 years). The cost-effectiveness analysis showed that the diagnostic scheme with gadoxetic acid was dominant because each disability-adjusted life year required fewer costs (14 862 rubles) in comparison with CT + MRI with extracellular GBCA (25 293 rubles) or CT (46 540 rubles). According to the results of the incremental cost-effectiveness ratio analysis, the application of the diagnostic complex with gadoxetic acid was characterized by the lowest rate of additional costs per 1 disability-adjusted life year.Conclusion. The pharmacoeconomic study showed that the application of MRI with a hepatospecific contrasting agent – gadoxetic acid in addition to contrast-enhanced CT was an effective and economically beneficial method of early HCC diagnosis.

Analysis of dynamic hepatobiliary contrast-enhanced MRI signal intensity after Yttrium-90 radioembolization with glass microspheres for the treatment of hepatocellular carcinoma.

To analyze hepatobiliary specific contrast agent (HBA) dynamic MRI signal intensity (SI) differences between treatedliver (TL) and untreated liver (UL) parenchyma in patients following transarterial radioembolization (TARE) for hepatocellular carcinoma (HCC) usingyttrium-90 containing glass microspheres. This was a single institution retrospective study of patients with HCC treated with lobar or segmental TARE who received pre- and post-treatment HBA multiphase MRI within a 3-year period. Patients with prior locoregional therapies or multiple TAREs were excluded. SI was obtained by drawing a 2D ROI on T1-weighted non-contrast, arterial (25s.), portal venous (60s.), transitional (180s.), and hepatobiliary (HB) (1200s.) phase sequences in the (TL) angiosome and UL. HB phase signal enhancement characteristics were correlated with TARE dose thresholds (< 120Gy, 120-190Gy, and > 190Gy)using the medical internal radiation dose (MIRD) methodology. 282 patients received TARE using glass microspheres during the study period and 58 patients who met inclusion criteria were analyzed. Median dose was 141.5Gy MIRD [IQR 122.0, 161.5; range 100-540Gy]). Statistically significant differences were present between treated and non-treated liver on non-contrast (-28.0, p = 0.003), arterial (38.5, p = 0.013), and HB phases (-95.8, p ≤ 0.001). Median follow-up time to furthest post-treatment MRI was 6 months (range 3-11 months).There was no significant SI difference on portal venous or transitional phases. HB phase SI changesin the TL compared to UL were significant at all TARE dose thresholds(p< 0.05). SI differences between treated and untreated liver after TARE are most significant on the HB phase and present at all evaluated dose levels at a median of 6 monthsafter treatment. These findings support the parenchymal ablative potential for TARE and the necessity to consider liver function loss within targeted liver volumes.

Unusual Distribution Kinetics of Gadoxetate in Healthy Human Subjects Genotyped for OATP1B1: Application of Population Analysis and a Minimal Physiological-Based Pharmacokinetic Model.

Gadoxetate (Gd-EOB-DTPA) isahepatobiliary-specific contrast agent for magnetic resonance imaging. Using a minimal physiological-based pharmacokinetic (PBPK) model, it has been shown for the first time, that the rapid initial decline of plasma concentration after intravenous injection is the result of an uptake into hepatocytes rather than of a distribution into the extravascular extracellular space. About 50% of the steady-state distribution volume is related to hepatic uptake. The hepatic extraction ratio and hepatic clearance estimated based on the liver model as a part of the PBPK model were in accordance with literature data. The same holds for the predicted time course of the amount of gadoxetate in liver parenchyma. In elucidating the impact of OATP1B1 genotype (*1a/*1a and *15/*15) on the pharmacokinetics of gadoxetate, we found that tissue uptake and back-transfer rates were significantly reduced, whereas the hepatic sinusoidal efflux rate was significantly increased in carriers of the *15/*15 haplotype compared with those of the *1a/*1a (wild type). Themodelispotentiallyuseful for determining hepatic kinetic parameters and distribution properties of drugs.

Predicting Therapeutic Efficacy of Vascular Disrupting Agent CA4P in Rats with Liver Tumors by Hepatobiliary Contrast Agent Mn-DPDP-Enhanced MRI

To evaluate hepatobiliary-specific contrast agent (CA) mangafodipir trisodium (Mn-DPDP)–enhanced magnetic resonance imaging (MRI) for predicting the therapeutic efficacy of the vascular disrupting agent combretastatin A4 phosphate (CA4P) in rats with primary and secondary liver tumors, 36 primary hepatocellular carcinomas (HCCs) were raised by diethylnitrosamine gavage in 16 male rats, in 6 of which one rhabdomyosarcomas (R1) was intrahepatically implanted as secondary liver tumors. On a 3.0T MR scanner with a wrist coil, tumors were monitored weekly by T2-/T1-weighted images (T2WI/T1WI) and characterized by Mn-DPDP-enhanced MRI. CA4P-induced intratumoral necrosis was depicted by nonspecific gadoterate meglumine (Gd-DOTA)–enhanced MRI before and 12 h after therapy. Changes of tumor-to-liver contrast (ΔT/L) on Mn-DPDP-enhanced images were analyzed. In vivo MRI findings were verified by postmortem microangiography and histopathology. Rat models of primary HCCs in a full spectrum of differentiation and secondary R1 liver tumors were successfully generated. Mn-DPDP-enhanced ΔT/L was negatively correlated with HCC differentiation grade (P < 0.01). After treatment with CA4P, more extensive tumoral necrosis was found in highly differentiated HCCs than that in moderately and poorly differentiated ones (P < 0.01); nearly complete necrosis was induced in secondary liver tumors. Mn-DPDP-enhanced MRI may help in imaging diagnosis of primary and secondary liver malignancies of different cellular differentiations and further in predicting CA4P therapeutic efficacy in primary HCCs and intrahepatic metastases.

Hepatocyte-specific contrast agent-enhanced magnetic resonance cholangiography: perioperative evaluation of the biliary tree.

A large number of gadolinium chelates have recently been tested in clinical trials. Some of those have already been approved for clinical use in the United States and Europe. Thus, new diagnostic perspectives have been incorporated into magnetic resonance imaging studies. Among such gadolinium chelates are hepatobiliary-specific contrast agents (HSCAs), which, due to their property of being selectively taken up by hepatocytes and excreted by the biliary ducts, have been widely used for the detection and characterization of focal hepatic lesions. In comparison with conventional magnetic resonance cholangiography (MRC), HSCA-enhanced MRC provides additional information, with higher spatial resolution and better anatomic evaluation of a non-dilated biliary tree. A thorough anatomic assessment of the biliary tree is crucial in various hepatic surgical procedures, such as complex resection in patients with colorectal cancer and living-donor liver transplantation. However, the use of HSCA-enhanced MRC is still limited, because of a lack of data in the literature and the poor familiarity of radiologists regarding its main indications. This pictorial essay aims to demonstrate the use of HSCA-enhanced MRC, with particular emphasis on anatomical analysis of the biliary tree, clinical applications, and the most important imaging findings.

Feasibility for detecting liver metastases in dogs using gadobenate dimeglumine-enhanced magnetic resonance imaging.

Early detection of liver metastases may improve the prognosis for successful treatment in dogs with primary tumors. Hepatobiliary-specific contrast agents have been shown to allow an increase in magnetic resonance imaging (MRI) detection of liver metastases in humans. The purpose of this prospective study was to test the feasibility for using one of these agents, gadobenate dimeglumine, to detect liver metastases in dogs. Ten consecutive dogs known to have a primary tumor were recruited for inclusion in the study. All dogs were scanned using the same protocol that included a T2-weighted respiratory-triggered sequence, T1 VIBE, diffusion-weighted imaging, and 3D-FLASH before and after dynamic injection of gadobenate dimeglumine contrast medium. Delayed imaging was performed less than 30 min after injection and up to 60 min in two cases. Histological analysis of liver lesions identified in delayed phases was performed for each case and confirmed metastatic origin. In all cases, lesion number detected in hepatobiliary contrast-enhanced sequences was statistically higher than in other sequences. Optimal lesion detection occurred with a 3D-FLASH sequence acquired in the transverse plane and less than 30 min after injection. Findings indicated that gabobenate dimeglumine enhanced MRI is a feasible technique for detecting liver metastases in dogs.

A new manganese-based oral contrast agent (CMC-001) for liver MRI: pharmacological and pharmaceutical aspects

Manganese is one of the most abundant metals on earth and is found as a component of more than 100 different minerals. Besides being an essential trace element in relation to the metabolic processes in the body, manganese is also a paramagnetic metal that possesses similar characteristics to gadolinium with regards to T1-weighted (T1-w) magnetic resonance imaging (MRI). Manganese, in the form of manganese (II) chloride tetrahydrate, is the active substance in a new targeted oral contrast agent, currently known as CMC-001, indicated for hepatobiliary MRI. Under physiological circumstances manganese is poorly absorbed from the intestine after oral intake, but by the use of specific absorption promoters, L-alanine and vitamin D(3), it is possible to obtain a sufficiently high concentration in the liver in order to achieve a significant signal enhancing effect. In the liver manganese is exposed to a very high first-pass effect, up to 98%, which prevents the metal from reaching the systemic circulation, thereby reducing the number of systemic side-effects. Manganese is one of the least toxic trace elements, and due to its favorable safety profile it may be an attractive alternative to gadolinium-based contrast agents for patients undergoing an MRI evaluation for liver metastases in the future. In this review the basic pharmacological and pharmaceutical aspects of this new targeted oral hepatobiliary specific contrast agent will be discussed.

Targeted MRI Contrast Agents for Pediatric Hepatobiliary Disease

New options are available for the magnetic resonance imaging (MRI) assessment of pediatric hepatobiliary disease. This article describes the potential utility for MRI with contrast agents tailored for hepatobiliary imaging. MRI contrast agents that preferentially target the liver may be helpful in characterizing liver masses and bile duct abnormalities in select children. The imaging approach is noninvasive and relatively rapid to perform. It also provides anatomic and functional information and is a radiation-free alternative to other imaging strategies. This relatively new imaging procedure is placed in the context of more established imaging modalities. The pharmacokinetics, technical considerations, and potential applications of these hepatobiliary-specific contrast agents also are discussed.

Contrast-enhanced MR cholangiography (MRCP) with GD-EOB-DTPA in evaluating biliary complications after surgery

We assessed the usefulness of contrast-enhanced magnetic resonance cholangiography (CE-MRC) with liver-specific contrast agent in evaluating the biliary tree after hepatic surgery. A total of 142 patients with suspected biliary complications after liver surgery underwent hepatobiliary MR before and after administration of gadolinium ethoxy benzylic diethylenetriamine pentaacetic acid (Gd-EOB-DTPA). Unenhanced MR cholangiopancreatography (MRCP) and postcontrast MRC were obtained in all patients. Blinded image evaluation and semiquantitative analysis comparing MRCP and CE-MRC were performed by two experienced radiologists. In all cases, optimal postcontrast visualisation of the biliary tract was obtained. In 22 patients, a postsurgical biliary complication was confirmed. MRCP detected 64% of lesions, but in 36% of cases, an alteration was only suspected but not clearly defined. CE-MRC allowed definite diagnosis in 100% of cases. Hepatobiliary-specific contrast agents allow for accurate and extensive study of biliary tract alterations, especially in assessing postsurgical complications.

Hepatobiliary-specific MR Contrast Agents: Role in Imaging the Liver and Biliary Tree

Hepatobiliary-specific contrast agents are one of several classes of contrast agents available for magnetic resonance (MR) imaging of the liver. These agents are taken up by functioning hepatocytes and excreted in the bile, and their paramagnetic properties cause shortening of the longitudinal relaxation time (T1) of the liver and biliary tree. The three contrast agents that have been developed are mangafodipir trisodium (Mn-DPDP), gadobenate dimeglumine (Gd-BOPTA), and gadoxetic acid (Gd-EOB-DTPA). These three MR contrast agents vary in mode of administration and dose, mechanism of cellular uptake, degree of excretion through the biliary pathway, and imaging characteristics. In the liver, hepatobiliary-specific agents can be used to improve lesion detection, to characterize lesions as hepatocellular or nonhepatocellular, and to specifically characterize some hepatocellular lesions, notably focal nodular hyperplasia. Biliary excretion of these agents can be used to evaluate the anatomic structure and function of the biliary tree. In the future, hepatobiliary-specific contrast agents may have wider applications, such as grading of cirrhosis and quantification of liver function.

MicroCT for high‐resolution imaging of ectopic pheochromocytoma tumors in the liver of nude mice

Successful outcomes for patients with cancer often depend on the early detection of tumor and the prompt initiation of active therapy. Despite major advances in the treatment of many cancers, early-stage lesions often go undetected due to the suboptimal resolution of current anatomical and functional imaging modalities. This limitation also applies to preclinical animal tumor models that are crucial for the evaluation and development of new therapeutic approaches to cancer. We report a new mouse model of metastatic pheochromocytoma, generated using tail vein injection of the mouse pheochromocytoma cell (MPC) line that reproducibly generated multiple liver tumors in the animals. Furthermore, we show that in vivo microCT imaging enhanced using a hepatobiliary-specific contrast agent, glyceryl-2-oleyl-1,3-di-7-(3-amino-2,4,6-triiodophenyl)-heptanoate (DHOG), detected tumors as small as 0.35 mm as early as 4 weeks after the injection of the tumor cells. This model may be useful for in vivo studies of tumor biology and for development of new strategies to treat metastatic pheochromocytoma.

The uptake of manganese dipyridoxal-diphosphate by chemically induced hepatocellular carcinoma in rats. A correlation between contrast-media-enhanced magnetic resonance imaging, tumor differentiation, and vascularization.

Negative enhancement of implanted liver tumors has been achieved in preclinical studies on manganese dipyridoxal-diphosphate (Mn-DPDP), a new hepatobiliary specific contrast agent for magnetic resonance imaging (MRI). The authors investigated the effects of Mn-DPDP on primary liver cancer and its possible mechanisms. Magnetic resonance imaging was performed in 15 rats with chemically induced hepatocellular carcinoma (HCC) before and after Mn-DPDP injection. Both tumor-liver contrast-to-noise ratio and absolute tumor enhancement were evaluated and compared with the MRI results of a nonspecific contrast agent, gadolinium-DOTA, and correlated with corresponding microangiographic and histologic findings. Mn-DPDP injection led to a persistent positive enhancement in differentiated solid HCCs (22/23) with maximal conspicuity at 24 hours. Undifferentiated HCCs were all delineated by a prompt negative enhancement (20/20) with maximal conspicuity within 30 minutes.

Mn-DPDP enhanced MRI in experimental bile duct obstruction.

To assess both the effect of Mn-DPDP as a hepatobiliary-specific contrast agent in bile duct obstruction and the relative role of liver and kidney in the elimination of this agent from the body, an animal experiment was set up. Twelve rats were used and divided into three groups. In group 1 the common bile duct was ligated, in group 2 bile duct ligation was limited to one lobe, and group 3 served as control. Magnetic resonance T1-weighted SE images were obtained before and after the injection of 25 mumol/kg of Mn-DPDP during the first 2 h and at day 1, 2, 3, 4, and, in some animals, up to 21 days. In normal rats the absolute enhancement signal-to-noise ratio (S/N) versus time plots obtained from the liver after Mn-DPDP injection returned to precontrast values within 24 h. In the group with common bile duct ligation, important liver enhancement persisted up to 21 days. In the group with selective obstruction, liver intensity normalized after 3 days. The S/N plots from spleen, renal cortex, and obstructed liver lobe showed similarities in time course. The present data indicate that Mn elimination is strongly impaired in the presence of bile duct obstruction. Renal glomerular filtration is ineffective in eliminating Mn from the body. The persisting splenic and renal cortical enhancement suggests that free Mn or some Mn-DPDP metabolite either is strongly bound to plasma proteins and acts as a blood pooling agent and/or is uptaken by the splenic or renal parenchyma.

Initial clinical experience with gadolinium bopta/dimeg: A new hepatobiliary specific contrast agent for magnetic resonance imaging (MRI) of the liver

Initial clinical experience with gadolinium bopta/dimeg: A new hepatobiliary specific contrast agent for magnetic resonance imaging (MRI) of the liver