Liver kinetics of glucose analogs measured in pigs by PET: importance of dual-input blood sampling.

Metabolic processes studied by PET are quantified traditionally using compartmental models, which relate the time course of the tracer concentration in tissue to that in arterial blood. For liver studies, the use of arterial input may, however, cause systematic errors to the estimated kinetic parameters, because of ignorance of the dual blood supply from the hepatic artery and the portal vein to the liver. METHODS: Six pigs underwent PET after [15O]carbon monoxide inhalation, 3-O-[11C]methylglucose (MG) injection, and [18F]FDG injection. For the glucose scans, PET data were acquired for 90 min. Hepatic arterial and portal venous blood samples and flows were measured during the scan. The dual-input function was calculated as the flow-weighted input. RESULTS: For both MG and FDG, the compartmental analysis using arterial input led to systematic underestimation of the rate constants for rapid blood-tissue exchange. Furthermore, the arterial input led to absurdly low estimates for the extracellular volume compared with the independently measured hepatic blood volume of 0.25 +/- 0.01 mL/mL (milliliter blood per milliliter liver tissue). In contrast, the use of a dual-input function provided parameter estimates that were in agreement with liver physiology. Using the dual-input function, the clearances into the liver cells (K1 = 1.11 +/- 0.11 mL/min/mL for MG; K1 = 1.07 +/- 0.19 mL/min/mL for FDG) were comparable with the liver blood flow (F = 1.02 +/- 0.05 mL/min/mL). As required physiologically, the extracellular volumes estimated using the dual-input function were larger than the hepatic blood volume. The linear Gjedde-Patlak analysis produced parameter estimates that were unaffected by the choice of input function, because this analysis was confined to time scales for which the arterial-input and dual-input functions were very similar. CONCLUSION: Compartmental analysis of MG and FDG kinetics using dynamic PET data requires measurements of dual-input activity concentrations. Using the dual-input function, physiologically reasonable parameter estimates of K1, k2, and Vp were obtained, whereas the use of conventional arterial sampling underestimated these parameters compared with independent measurements of hepatic flow and hepatic blood volume. In contrast, the linear Gjedde-Patlak analysis, being less informative but more robust, gave similar parameter estimates (K, V) with both input functions.     

Bringing physiology into PET of the liver

Several physiologic features make interpretation of PET studies of liver physiology an exciting challenge. As with other organs, hepatic tracer kinetics using PET is quantified by dynamic recording of the liver after the administration of a radioactive tracer, with measurements of time-activity curves in the blood supply. However, the liver receives blood from both the portal vein and the hepatic artery, with the peak of the portal vein time-activity curve being delayed and dispersed compared with that of the hepatic artery. The use of a flow-weighted dual-input time-activity curve is of importance for the estimation of hepatic blood perfusion through initial dynamic PET recording. The portal vein is inaccessible in humans, and methods of estimating the dual-input time-activity curve without portal vein measurements are being developed. Such methods are used to estimate regional hepatic blood perfusion, for example, by means of the initial part of a dynamic (18)F-FDG PET/CT recording. Later, steady-state hepatic metabolism can be assessed using only the arterial input, provided that neither the tracer nor its metabolites are irreversibly trapped in the prehepatic splanchnic area within the acquisition period. This is used in studies of regulation of hepatic metabolism of, for example, (18)F-FDG and (11)C-palmitate.     

Hepatic perfusion CT imaging analyzed by the dual-input one-compartment model

AIM: To improve liver-perfusion imaging by using the dual-input one-compartmental model. METHODS: Single-level dynamic computed tomography (dynamic CT) was taken at the height of the hepatic hilum after a rapid intravenous injection using 40 ml of iodinated contrast material. From the time-density curve of each pixel on CT, we calculated blood-flow rate constants of liver inflow and outflow. For inflow, two constants were calculated at arterial and portal veins. We postulated that blood flow between hepatic vessels and the hepatic parenchyma could be analyzed by using the calculated constants, and made equations for liver perfusion mapping. The perfusion images obtained by this method were compared with those made by the maximum slope method. RESULTS: We applied the method to a patient with hepatolithiasis. On dynamic CT, there was an abnormal enhancement pattern in the posterior segment of the liver. Perfusion CT images made by the dual-input one-compartment model demonstrated abnormal portal perfusion of the liver. In contrast, those made by the maximum-slope method did not represent the perfusion pattern well. CONCLUSION: The dual-input one-compartmental model makes it possible to obtain more detailed information on liver hemodynamics.     

Dynamic contrast-enhanced CT imaging of hepatocellular carcinoma in cirrhosis: feasibility of a prolonged dual-phase imaging protocol with tracer kinetics modeling

Dynamic contrast-enhanced (DCE) CT imaging of four patients with hepatocellular carcinoma (HCC) was performed using a dual-phase imaging protocol designed with initial rapid dynamic imaging to capture the initial increase in contrast medium enhancement in order to assess perfusion, followed by a delayed imaging phase with progressively longer intervals to monitor subsequent tissue enhancement behaviour in order to assess tissue permeability. The DCE CT images were analysed using a dual-input two-compartment distributed parameter model to yield separate estimates for blood flow and permeability, as well as fractional intravascular and extravascular volumes. The HCCs and surrounding cirrhotic liver tissues were found to exhibit enhancement curves that can be appropriately described by two distinct compartments separated by a semipermeable barrier. Early contrast arrival was also found for HCC as compared with background liver. These findings are consistent with the current understanding of sinusoidal capillarization and hepatocarcinogenesis.     

Pharmacokinetic parameters in CNS Gd-DTPA enhanced MR imaging

Dynamic MR imaging can be used to study tissue perfusion and vascular permeability. In the present article a procedure for dynamic MR is presented, which (a) accurately resolves the fast kinetics of tissue response during and after intravenous infusion of the paramagnetic contrast medium Gd-DTPA and (b) yields a linear relationship between the measured MR signal and the Gd-DTPA concentration in the tissue. According to these features, the measured signal-time curves can be analyzed within the framework of pharmacokinetic modeling. Tissue response has been parameterized using a linear two-compartment open model, with only negligible effects of the peripheral compartment on the central compartment. The three model parameters were fitted to the signal-time data pixel by pixel, based on a set of 64 rapid SE images (SE 100/10 ms, image scan time 13 s, interscan intervals 11 s). This makes it possible to construct parameter images, whereby structures become visible that cannot be distinguished in conventional Gd-DTPA enhanced MR. As a clinical example, the approach is discussed in a case of glioblastoma.     

Dynamic susceptibility contrast MRI with localized arterial input functions

Compared to gold‐standard measurements of cerebral perfusion with positron emission tomography using H₂[¹⁵O] tracers, measurements with dynamic susceptibility contrast MR are more accessible, less expensive, and less invasive. However, existing methods for analyzing and interpreting data from dynamic susceptibility contrast MR have characteristic disadvantages that include sensitivity to incorrectly modeled delay and dispersion in a single, global arterial input function. We describe a model of tissue microcirculation derived from tracer kinetics that estimates for each voxel a unique, localized arterial input function. Parameters of the model were estimated using Bayesian probability theory and Markov‐chain Monte Carlo, circumventing difficulties arising from numerical deconvolution. Applying the new method to imaging studies from a cohort of 14 patients with chronic, atherosclerotic, occlusive disease showed strong correlations between perfusion measured by dynamic susceptibility contrast MR with localized arterial input function and perfusion measured by quantitative positron emission tomography with H₂[¹⁵O]. Regression to positron emission tomography measurements enabled conversion of dynamic susceptibility contrast MR to a physiologic scale. Regression analysis for localized arterial input function gave estimates of a scaling factor for quantitation that described perfusion accurately in patients with substantial variability in hemodynamic impairment. Magn Reson Med 63:1305–1314, 2010. © 2010 Wiley‐Liss, Inc.     

Methods for quantitative assessment of tissue microcirculation using dynamic contrast-enhanced MR imaging

Summary The development of rapid magnetic resonance imaging (MRI) sequences makes it possible to detect the fast kinetics of tissue response after intraveneous administration of paramagnetic contrast media (CM), reflecting the status of tissue microcirculation. In this paper, the basic physical and tracer kinetic principles of dynamic relaxivity and susceptibility contrast MRI techniques are reviewed. The quantitative analysis of the acquired dynamic image data is broken up into an MR specific part, in which the observed signal variations are related to the CM concentration in the tissue, and an MR independent part, in which the computed concentration-time-courses are analyzed by tracer kinetic modeling. The purpose of the applied models is to describe the underlying physiological processes in mathematical terms and thus to enable the estimation of tissue specific parameters from measured dynamic image series. Whereas the capillary permeability can be estimated from dynamic relaxivity contrast enhanced MRI studies, the regional blood volume as well as the regional blood flow can be determined from dynamic susceptibility contrast enhanced image series. However, since there are no intravascular but only diffusible CM available at present, the application of the susceptibility technique is currently restricted to brain tissues with intact blood brain barrier. The practical realization of both dynamic MRI techniques is demonstrated by case studies. Eingegangen am 5. M?rz 1997 Angenommen am 24. April 1997     

The utility of quantitative 99mTc-GSA liver scintigraphy in the evaluation of hepatic functional reserve: comparison with 99mTc-PMT and 99mTc-Sn colloid]

Using data from 17 patients with liver cirrhosis and 3 patients with fatty liver, we have compared the utility of 3 hepatic imaging agents in the evaluation of hepatic functional reserve. Evaluated here were 99mTc-galactosyl human serum albumin (GSA) which is a new ligand for hepatic binding protein, 99mTc-N-pyridoxyl-5-methyl tryptophan (PMT) of a hepatobiliary agent, and 99mTc-Sn colloid. In each patient, we performed these 3 imaging studies within a week and also examined hepatic function tests (indocyanine green test, hepaplastin test, choline-esterase, etc). In each imaging study, serial images and dynamic data were obtained after the injection of 99mTc-GSA (185 MBq/3 mg), 99mTc-PMT (185 MBq), or 99mTc-Sn colloid (185 MBq). Using the obtained dynamic data, we analyzed the liver kinetics of the 3 agents based on 1 compartment model with 3 parameters (hepatic clearance, hepatic excretion rate, non-specific volume of distribution). From fitting the liver and heart data to this model, three unknown parameters were determined. Patlak plot was also applied in order to estimate liver uptake rate. Both curve fitting and Patlak plot could determine appropriate parameters in every study. In 99mTc-GSA, a nonlinear 3 compartment model was also applied in order to estimate hepatic blood flow, liver receptor density, and affinity of receptor-GSA binding separately. Using the obtained parameters, we analyzed the correlations between the parameters and the results of hepatic function tests. In all of the parameters, those obtained from 99mTc-GSA imaging showed the most significant statistical correlation with the results of hepatic function tests. From the present results, 99mTc-GSA imaging was concluded to be the best for evaluation of hepatic functional reserve.     

Application of superparamagnetic iron oxide to imaging of hepatocellular carcinoma

Superparamagnetic iron oxide (SPIO) particles are as MR contrast media composed of iron oxide crystals coated with dextran or carboxydextran. These particles are sequestered by phagocytic Kupffer cells in normal reticuloendothelial system (RES), but are not retained in tumor tissue. Consequently, there are significant differences in T2/T2* relaxation between normal RES tissue and tumors, which result in increased lesion conspicuity and detectability. The introduction of SPIO has been expected to substantially increase the detectability of hepatic metastases. For focal hepatocellular lesions, it has been documented that SPIO-enhanced MR imaging exhibits slightly better diagnostic performance than dynamic helical CT in the detection of hypervascular hepatocellular carcinoma (HCC). A combination of dynamic and static MR imaging technique using T1- and T2 imaging criteria appears to provide clinically more useful patterns of enhancement. SPIO-enhanced MR imaging also provides information useful for differential diagnosis, via enhancement of RES-containing tumors. With the exploitation of rapid T2*-sensitive sequences, SPIO-enhanced dynamic MR imaging may become comparable to gadolinium-enhanced dynamic MR imaging and dynamic studies with multidetector-row CT. SPIO-enhanced MR imaging plays an important role in therapeutic decision-making for patients with HCC.     

MRI measurement of hepatic magnetic susceptibility-phantom validation and normal subject studies.

A magnetic resonance (MR) imaging method with the potential for assessing hepatic iron overload from measurements of hepatic magnetic susceptibility in vivo is described. Using the blood in the portal and hepatic veins as an internal reference, this technique uses the orientation dependence of signal phase to measure the susceptibility of the liver parenchyma. Computer simulations were done to investigate the requirements on spatial resolution and contrast ratio between the vessels and the background liver tissue for data acquisition. Validation studies were conducted using tube-embedded gel phantoms doped with iron-dextran from 0 to 10 mg Fe/mL to mimic healthy and iron-overloaded livers. The phantom measurements were conducted without motion and flow, under respiration-like oscillatory motion, and with flow. Studies on six normal human subjects demonstrated excellent reproducibility and precision. All images were collected at 1.5 T using a 3D T(1)-weighted turbo field echo sequence for inflow MR angiographies with full flow compensation and capable of cardiac synchronization, navigator gating, and motion correction.     

Kontrastmittelverstärkte Magnetresonanztomographie von Lebermetastasen: Positive versus negative Kontrastmittel

The development in oncologic liver surgery as well as modified interventional therapy strategies of the liver have resulted in improved diagnostic imaging. The evolution of contrast agents for MR imaging of the liver has proceeded along several different paths with the common goal of improving liver-lesion contrast. In MRI contrast agents act indirectly by their effects on relaxation times. Contrast agents used for hepatic MR imaging can be categorized in those that target the extracellular space, the hepatobiliary system, and the reticuloendothelial system. The first two result in a positive enhancement, the last one in a negative enhancement. Positive enhancers allow a better characterization of liver metastases using dynamic sequence protocols. Detection rate of liver metastases is increased using hepatobiliary contrast-enhanced MRI compared to unenhanced MRI. Negative enhancers, iron oxide particles, significantly increase tumor-to-liver contrast and allow detection of more lesions than other diagnostic methods. Iron-oxide enhanced MRI enables differential diagnosis of liver metastases comparing morphologic features using T2 and T1-weighted sequences.     

动态及延时增强磁共振成像对肝血管瘤诊断的评价

目的:研究动态增强及延迟增强扫描磁共振成像对肝血管瘤的诊断价值。材料和方法:34例肝血管瘤病人行常规MRT1WI、T2WI横断面扫描。经肘静脉手推团注0.1mmol/kg体重Gd-DTPA后,再推入10ml生理盐水冲洗后(推入时间5~6s)行射频毁坏傅立叶采集稳态技术T1WI动态增强扫描及延迟增强扫描,分析病灶及邻近肝实质增强。结果:共发现肝血管瘤病灶67个。动态增强见46个病灶呈边缘不连续样的结节样强化,21个病灶呈周边不规则强化或迅速强化充填;5个病灶动态增强早期见引流静脉强化,14个瘤周肝实质强化。延迟增强扫描见53个病灶完全充填强化,14个病灶显示斑片状或裂隙状的低信号未充填区。结论:在磁共振成像检查中,动态增强扫描能够显示肝血管瘤及邻近实质强化方式,延迟增强显示病灶的充填程度,两者结合更有利于肝血管瘤的诊断。     

Transverse relaxation effect of MRI contrast agents: a crucial issue for quantitative measurements of cerebral perfusion

Quantitative cerebral perfusion imaging using dynamic susceptibility contrast (DSC) MRI requires the dynamic measurement of changes in contrast agent concentration in cerebral tissue and its feeding artery. In this work the tracer kinetics approach to general tracer-based perfusion imaging is reviewed. In the typical practical setting, measurements of change in transverse relaxation (DeltaR(2)) derived from MR signals are assumed to be substitutes for true concentration measurements. The implications and limitations of this assumption are reviewed in the light of various results obtained in theoretical, simulated, and experimental studies. The mechanisms of R(2) changes in biological media are discussed. These mechanisms operate over different spatial scales and differentially influence gradient-echo (GE) and spin-echo (SE) MRI signals. This differential sensitivity can be used to assess vessel size in the microvasculature. Finally, the need for well controlled experimental data to provide input parameters and/or experimental tests of theoretical models is emphasized.     

Local tumor recurrence following hepatic cryoablation: radiologic-histopathologic correlation in a rabbit model

PURPOSE: To use radiologic-histopathologic correlation in an animal model to distinguish normal postoperative findings from evidence of residual tumor after cryoablation of malignant hepatic tumors. MATERIALS AND METHODS: Hepatic cryoablation was performed in 12 rabbits with VX2 tumors and in two healthy rabbits. Nonenhanced and dynamic contrast material-enhanced computed tomography (CT) and magnetic resonance (MR) imaging and power and color Doppler flow ultrasonography (US) were performed 7-8 days after cryoablation. Histopathologic findings were correlated with imaging findings. RESULTS: Twenty tumors of 5-20 mm (mean, 10 mm) and seven areas of normal liver were treated with cryolesions of 11-21 mm (mean, 15 mm). All cryolesions exhibited arterial phase rim enhancement at CT and MR imaging, and 13 (57%) of 23 lesions demonstrated peripheral flow at US because of granulation tissue. There was macroscopic recurrence in 15 (75%) of 20 treated tumors; 14 (93%) appeared as peripheral nodularity with low-grade enhancement. Necrotic tissue did not enhance. Intact vessels extended up to 6 mm inside cryolesion margins and caused focal internal enhancement and Doppler flow. Areas of high signal intensity on T2-weighted MR images correlated with liquefaction necrosis, granulation tissue, and tumor. CONCLUSION: In this animal model, recurrent tumor typically appeared as focal nodules at the cryolesion periphery. Rim and central foci of enhancement, Doppler flow, and increased signal intensity on T2-weighted MR images can be normal findings after hepatic cryoablation.     

Hepatocellular adenoma: diagnostic difficulties and novel imaging techniques

We report the case of a 30-year-old eastern European female who presented with right upper quadrant pain. Clinical examination was unremarkable and liver function tests were normal. CT identified a 5 cm lesion in segment V of the liver, which was of homogeneous low density with no calcification or significant enhancement. MRI showed the lesion to be hypointense to liver on T(1) weighted sequences and isointense on T(2) weighted sequences. Rapid arterial enhancement with gadolinium-DTPA faded without leaving a definite central scar. Ultrasound showed the lesion to be echogenic with minimal vascularity. Administration of a liver-specific microbubble contrast agent showed low uptake relative to the surrounding liver. Phosphorus-31 MR spectroscopy, localized to the lesion itself, revealed a markedly increased phosphomonoester resonance with a decreased phosphodiester resonance, compatible with increased cell turnover. Biopsy confirmed the lesion to be a hepatocellular adenoma. The diagnosis of a hepatic adenoma is difficult with tissue diagnosis the gold standard, but it may be suggested by a combination of imaging modalities. We have described two new imaging techniques not previously described in characterization of hepatic adenomata, namely ultrasound with contrast agent and MR spectroscopy.     

Optimal k‐space sampling for dynamic contrast‐enhanced MRI with an application to MR renography

For time‐resolved acquisitions with k‐space undersampling, a simulation method was developed for selecting imaging parameters based on minimization of errors in signal intensity versus time and physiologic parameters derived from tracer kinetic analysis. Optimization was performed for time‐resolved angiography with stochastic trajectories (TWIST) algorithm applied to contrast‐enhanced MR renography. A realistic 4D phantom comprised of aorta and two kidneys, one healthy and one diseased, was created with ideal tissue time‐enhancement pattern generated using a three‐compartment model with fixed parameters, including glomerular filtration rate (GFR) and renal plasma flow (RPF). TWIST acquisitions with different combinations of sampled central and peripheral k‐space portions were applied to this phantom. Acquisition performance was assessed by the difference between simulated signal intensity (SI) and calculated GFR and RPF and their ideal values. Sampling of the 20% of the center and 1/5 of the periphery of k‐space in phase‐encoding plane and data‐sharing of the remaining 4/5 minimized the errors in SI (<5%), RPF, and GFR (both <10% for both healthy and diseased kidneys). High‐quality dynamic human images were acquired with optimal TWIST parameters and 2.4 sec temporal resolution. The proposed method can be generalized to other dynamic contrast‐enhanced MRI applications, e.g., MR angiography or cancer imaging. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Quantification of [(18)F]FDG uptake in the normal liver using dynamic PET: impact and modeling of the dual hepatic blood supply.

For quantification of hepatic [(18)F]FDG uptake, the dual blood supply to the liver must be considered. In contrast to the arterial input, however, the portal venous blood supply to the liver cannot be monitored directly by PET because of the inaccessibility of the portal vein on PET scans. In this study, we investigated whether the dual hepatic input can be predicted from the measurable arterial input. Moreover, we assessed the effect of different input models on the rate constants of the standard 3-compartment model describing regional uptake of FDG. METHODS: Dynamic FDG PET scanning was performed on 5 foxhounds. Activity concentrations in blood from the aorta and the portal vein were measured simultaneously using external circuits. After image reconstruction, time--activity courses were determined from the aorta and the liver. The venous input was approximated by convolving the arterial input with a notional system function describing the dispersion of the arterial input on its way through the gastrointestinal tract. On the basis of these data, 5 different hepatic input models, which pertain to a single-input as well as a dual-input scenario, were statistically compared with regard to the adequacy of the model fits to liver data and to differences in the estimated rate constants. RESULTS: Portal venous input to the liver could be approximated by convolving the arterial input function with a system function. From this function, a mean transit time of 25 s was computed for FDG to pass through the gastrointestinal tract. According to the statistical analysis, dual-input models were superior to their single-input counterparts. However, differences in the rate constants estimated for the 5 input models were in the same order as interindividual variations within the different model groups. For the dephosphorylation rate constant, a consistent value of 0.05 +/- 0.01 min(-1) was found. CONCLUSION: Dual-input models proved to be superior to single-input models with respect to the adequacy of FDG model fits to normal liver data. However, the hepatic blood supply may be approximated by the arterial input function as well, especially for the evaluation of liver lesions mainly fed by the hepatic artery.     

Measurement of liver blood flow using oxygen-15 labelled water and dynamic positron emission tomography: Limitations of model description

To date no satisfactory method has been available for the quantitative in vivo measurement of the complex hepatic blood flow. In this study two modelling approaches are proposed for the analysis of liver blood flow using positron emission tomography (PET). Five experiments were performed on three foxhounds. The anaesthetised dogs were each given an intravenous bolus injection of oxygen-15 labelled water, and their livers were then scanned using PET. Radioactivity in the blood from the aorta and portal vein was measured directly and simultaneously using closed external circuits. Time-activity curves were constructed from sequential PET data. Data analysis was performed by assuming that water behaves as a freely diffusible tracer and adapting the standard one-compartment blood flow model to describe the dual blood supply of the liver. Two particular modelling approaches were investigated: the dual-input model used both directly measured input functions (i.e. using the hepatic artery and the portal vein input, determined from the radioactivity detected in the aorta and portal vein respectively) whereas the single-input model used only the measured arterial curve and predicted the corresponding portal input function. Hepatic arterial flow, portal flow and blood volume were fitted from the PET data in several regions of the liver. The resulting estimates were then compared with reference blood flow measurements, obtained using a standard microsphere technique. The microspheres were injected in a separate experiment on the same dogs immediately prior to PET scanning. Whilst neither the single- nor the dual-input models accurately reproduced the arterial reference flow values, the flow values from the single-input model were closer to the microsphere flow values. The proposed single-input model would be a good approximation for liver blood flow measurements in man. The observed discrepancies between the PET and microsphere flow values may be due to the inherent temporal and spatial heterogeneity of liver blood flow. The results presented suggest that adaptation of the standard one-compartment blood flow model to describe the dual blood supply of the liver is limited and other flow tracers have to be considered for quantitative PET measurements in the liver.     

Receptor-directed contrast agents for MR imaging: preclinical evaluation with affinity assays.

In this study, the target-specific behavior of magnetic resonance (MR) imaging contrast agents directed at human hepatic asialoglycoprotein (ASG) receptors was evaluated in vitro with use of two novel assays: relaxation time measurements of incubated human cell membrane solutions and iron staining of biopsy samples. Specific uptake of ASG receptor-directed agents was demonstrated in human samples of normal liver tissue, areas of hepatitis, regenerating nodules, areas of focal nodular hyperplasia, and hepatic adenomas. A conventional iron oxide preparation not directed at ASG receptors failed to demonstrate specific uptake in these tissues. Attachment of the ASG receptor-directed agents was competitively blocked with a receptor agonist (D(+)-galactose) in these tissues. No attachment of conventional or receptor agents was seen in areas of hepatocellular carcinoma, cholangiocarcinoma, or liver metastases. The studies indicate that in vitro receptor assays are useful in predicting the affinity of new receptor-directed MR imaging contrast agents in human tissue prior to clinical trials.