Consensus report from the 6th International forum for liver MRI using gadoxetic acid

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108276/1/jmri24419.pd

Cystic fibrosis related chronic liver disease: a study of its influence upon prognosis and possible mechanisms for this; with specific reference to pulmonary and systemic haemodynamics

MDTo assess the influence of chronic liver disease on survival a time dependent multivariate Cox regression analysis was It performed. The results confirmed that patients with evidence of chronic liver disease have a worse prognosis. The effect of liver disease upon survival was not related to hepatic decompensation, as only 2.2% of deaths were liver-related, suggesting an occult adverse effect. To establish a non-invasive means for the diagnosis of chronic liver disease an ultrasound scoring system was developed, and validated for reproducibility by two independent radiologists. This scoring system correlated well with the capacity of the liver to metabolise lignocaine to monoethylglycine xylidide, with fasting serum bile acids and with the PGA index. While the measurement of the N-terminal propeptide of procollagen III revealed significant differences between subjects with and without liver disease, the results correlated less well with the ultrasound score. Abnormalities documented by quantitative hepatobiliary scintigraphy also correlated well with the ultrasound based scoring system. Having established suitable criteria for diagnosing chronic liver disease in cystic fibrosis the systemic and pulmonary 2 circulations of patients with and without liver disease were evaluated non-invasively. The results confirm the presence of a hyperdynamic circulatory state in patients with chronic liver disease with significant elevations of cardiac output and left ventricular stroke work index and reductions of mean arterial pressure and systemic vascular resistance index. There were no differences in the peripheral circulatory status of the two cohorts. Evaluation of the pulmonary circulation was made using shuntperfusion scans and the 100% oxygen re-breathing technique. Significant pulmonary arterio-venous shunting, consistent with a diagnosis of the 'hepato-pulmonary' syndrome, was only detected in the cohort with liver disease (36% of those studied). The results of studies presented within this thesis suggest that chronic liver disease can be confidently detected using ultrasound criteria, is important in the prognosis of patients with cystic fibrosis due to its covert adverse effect on survival, and may exert some of these effects through systemic and pulmonary circulatory changes

Post Hepatectomy Liver Failure: Risk Factors and Prediction of Post-Operative Function using Novel Dynamic MRI

Liver surgery is an advancing specialty with improved outcomes in recent years. Liver resection is used with curative intent for both primary and metastatic cancer. Despite the rapid improvements and increasing range of surgical options, there remains a significant risk of developing Post-Hepatectomy Liver Failure (PHLF) – caused by inadequate remnant liver function after surgery. This is a condition with high mortality and morbidity and currently there are no specific treatments for it once it has developed. Its pathogenesis is complex and multifactorial, and some risk factors, particularly ageing are uncertain as to their contributing significance. This thesis aimed to investigate risk factors for PHLF development and a imaging based measurement of liver function after major liver resection. This study identified patients over-75 years have a significantly increased risk of PHLF. Development of a method to predict post-operative function is needed to aid patient selection and reduce complications for those who undergo resection. Currently, volumetry is performed but this has proven inadequate, with some patients still developing PHLF despite adequate remnant volume. Other options such as Indocyanine Green and Technetium-99m labelled Mebrofenin are not readily available. One potential solution is Dynamic Gadoxetate Enhanced (DGE) MRI of the Liver, which has been developed to investigate liver function, with promising results for demonstrating liver heterogenicity in patients with parenchymal liver diseases. Oncological staging of the liver involves MRI to plan surgical resection, and DGE-MRI can be integrated into the diagnostic protocol easily with no additional burden to the patient. This thesis aimed to demonstrate if DGE-MRI functional estimates can predict post-operative liver function after resection of colorectal liver metastases. This study demonstrated that there was good correlation of DGE-MRI-function tests with post-operative hyperbilirubinaemia, a measure of hepatic dysfunction. This could be utilised in surgical planning to improve patient selection and outcomes

Functional liver-image guided hepatic therapy (FLIGHT): A technique to maximize hepatic functional reserve

Introduction: Radiation planning approaches for liver radiation often do not consider the regional variation that can exist in liver function. This study dosimetrically compares functional liver image-guided hepatic therapy (FLIGHT) to standard stereotactic body radiation therapy (SBRT) plans. In the FLIGHT plans, functional data from hepatobiliary iminodiacetic acid (HIDA) single photon emission computed tomography (SPECT) scans serve as a road map to guide beam arrangement. While meeting the same target volume coverage, plans are optimized to reduce dose to high-functioning liver. Materials and Methods: The study included 10 patients with hepatocellular carcinoma (HCC) with baseline HIDA SPECT imaging. Standard SBRT plans which did not systematically incorporate these scans had previously been completed on all 10 plans. Retrospectively, FLIGHT plans were created based on the use of contours of relative liver function from the HIDA SPECT as avoidance structures. Resulting dose to each relative functional liver structure was examined and compared qualitatively and using Wilcoxin rank-sum tests. Target coverage, doses to organs at risk (OARs), conformity index (CI), and gradient index (GI) were also evaluated. Results: While maintaining the same target coverage, FLIGHT plans reduced the mean dose to the high functioning liver by a median of 3.0 Gy (range 0.7 to 4.6 Gy), which represented a 31.4% mean reduction compared to standard planning. FLIGHT plans reduced the volume of high functioning liver receiving 15 Gy by a mean of 59.3 cc (range 7 to 170 cc), for a mean reduction of 41.9%. The mean dose to areas of liver function defined by 25% to 100% and 50% to 100% maximum was reduced with FLIGHT from 10.5 Gy to 8.5 Gy and from 10.5 Gy to 7.5 Gy, respectively ( p < 0.005 for both comparisons). The FLIGHT plans’ mean CI and GI did not differ significantly from the standard plans’ ( p = 0.721 and 0.169, respectively). Conclusion: FLIGHT SBRT allows for field design and plan optimization individualized to a patient's baseline regional liver function to maximize hepatic functional reserve. This personalized approach is achieved without compromising target coverage or OAR sparing

Magnetic resonance imaging for the assessment of liver function

This thesis presents dynamic hepatocyte-specific contrast-enhanced magnetic resonance imaging (DHCE-MRI) as a new method for total and segmental liver function assessment. The method is based on the hepatocyte-specific properties of Gd- EOB-DTPA, which is actively taken up into functioning hepatocytes. The presence of this substance in a tissue will induce an increase in signal intensity in magnetic resonance imaging (MRI). The underlying hypothesis in this work is that if the liver uptake of Gd-EOB-DTPA could be quantified, this would then reflect liver function. All studies were approved by the Stockholm Regional Ethical Review Board. The first study was performed on 20 healthy volunteers and showed that quantification of tracer uptake and liver perfusion was feasible on a segmental level using deconvolutional analysis (DA). In the second study, quantification of tracer uptake was done in 12 patients with primary biliary cirrhosis (PBC) as well as in the 20 healthy controls examined in the first study. Both quantitative parameters derived from DA and traditional semi-quantitative parameters (Cmax, tmax, t1/2) were assessed. There were significant differences in the DA-derived parameters regarding uptake capacity and tracer transfer time between PBC patients and controls, but the traditional semiquantitative parameters were not able to separate the groups. Furthermore, there was a significant association between established prognostic scoring-models and the quantitative parameters. In the third study the healthy volunteers from the first study were again used as controls, but this time compared to 12 patients with primary sclerosing cholangitis (PSC). Total and segmental liver function as well as volume was assessed using DA-derived quantitative parameters, but no significant differences between the groups were found. A significantly more heterogeneous distribution of liver function was found in the PSC group, and the degree of bile duct stricturing so typical of PSC was found to correlate with the DA-derived liver function parameters. In the fourth study total and segmental liver function was assessed in 10 patients with varying degrees of alcohol- and/or viral-induced cirrhosis, and compared to the controls of the first study. Also in this patient group a significantly more heterogeneous distribution of liver function was found, as well as significant differences between the groups regarding the outcome of the functional parameters. In a simulation of a left hemihepatectomy, the possible implication of this heterogeneous distribution of function on liver resection was assessed, showing how uncertain the prediction of postoperative liver function can be when regional differences in liver function are not accounted for. In a receiver operator characteristic (ROC) analysis, the DHCE-MRI derived parameters showed good to excellent capacity in separating groups with normal or adequate liver function from patients with more severely affected liver parenchyma. In conclusion, DHCE-MRI can be used to assess total and segmental liver volume and function. Functional parameters indicative of parenchymal tracer extraction capacity, liver perfusion and tracer transit times can also be assessed on a global and segmental level. The outcome of these parameters differs significantly between patients with liver cirrhosis and healthy controls, and also correlates with established clinical scoring models. DHCE-MRI is a new and promising tool for total and segmental liver function assessment and deserves further studies

Investigation of probe substrates to assess hepatic transport function

The objective of this research project was to identify and characterize probe substrates for specific hepatic transport proteins. Identification of specific probe substrates for basolateral and canalicular transport proteins is necessary to elucidate mechanisms of hepatobiliary drug transport, phenotype for interindividual differences in transport protein function, and identify potential drug-drug interactions at the hepatic transport level. Three probe substrates were selected for investigation: fexofenadine, 99mTechnetium mebrofenin (99mTc-MEB), and 99mTechnetium sestamibi (99mTc-MIBI). Although fexofenadine has been touted as a P-gp specific probe substrate, pharmacokinetic modeling/siumulation of clinical data, sandwich-cultured human hepatocyte experiments and perfused liver studies in rats and mice demonstrated that fexofenadine is not a suitable probe for a specific transport protein due to compensatory efflux pathways. The hepatic uptake and excretion of 99mTc-MEB and 99mTc-MIBI have not been investigated fully despite their use as non-invasive probes to assess transport function. Therefore, suspended and sandwich-cultured rat and human hepatocytes were used to fully characterize the mechanisms of hepatic transport of 99mTc-MEB and 99mTc-MIBI. Then to validate the use of 99mTc-MEB and/or 99mTc-MIBI as probe substrates to predict the hepatic clearance of the anticancer agent, sorafenib studies were conducted to confirm similar mechanisms of hepatic uptake. Lastly, the pharmacokinetics and hepatic exposure of 99mTc-MIBI and 99mTc-MEB were compared in a patient with hepatocellular carcinoma and Child's Pugh B cirrhosis vs. healthy human volunteers. Pharmacokinetic models were constructed to describe the distribution and elimination of 99mTc-MEB and 99mTc-MIBI, to compare alterations in key rate constants representing hepatic uptake and efflux mechanisms secondary to disease. In conclusion, 99mTc-MEB and 99mTc-MIBI may be very useful phenotypic probes that are sensitive to changes in hepatic function associated with liver disease. The hepatic exposure to 99mTc-MIBI was decreased in the patient with hepatocellular carcinoma and cirrhosis compared to healthy volunteers, whereas the hepatic exposure of 99mTc-MEB was similar but the hepatic exposure profile was notably different with a lower maximum but more prolonged exposure. Collectively, the results of this research negate the use of fexofenadine as a probe for hepatic transport, but support the use of 99mTc-MEB and 99mTc-MIBI as probe substrates, which add the unique ability to quantify liver concentrations

Diagnostic interventions in nuclear medicine

Diagnostic interventions in nuclear medicine may be defined as the coadministration of a nonradioactive drug or application of a physical stimulus or physiologic maneuver to enhance the diagnostic utility of a nuclear medicine test. The rationale for each interventional maneuver follows from the physiology or metabolism of the particular organ or organ system under evaluation. Diagnostic inference is drawn from the pattern of change in the biodistribution of the tracer in response to the intervention-induced change in metabolism or function.In current practice, the most commonly performed interventional maneuvers are aimed at studies of the heart, genitourinary system, hepatobiliary system, and gastrointestinal tract. The single most commonly performed interventional study in the United States is the stress Thallium-201 myocardial perfusion scan aimed at the diagnosis of coronary artery disease. The stress portion of the study is accomplished with dynamic leg exercise on a treadmill and is aimed at increasing myocardial oxygen demands. Areas of myocardium distal to hemodynamically significant lesions in the coronary arteries become ischemic at peak stress due to the inability of the stenotic vessel to respond to the oxygen demand/blood flow needs of the myocardium. Ischemic areas are readily recognized as photopenic defects on scans obtained immediately after exercise, with "normalization" upon delayed imaging.Diuresis renography is aimed at the differential diagnosis of hydroureteronephrosis. By challenging the urinary tract collecting structures with an augmented urine flow, dilated, unobstructed systems can be differentialed from systems with significant mechanical obstruction. Obstructed systems have a low ability to respond even after effective diuresis, resulting in a characteristic prolonged retention of the radiotracer.Hepatobiliary interventions are most commonly employed in the clinical setting of suspected acute cholecystitis. Administering a cholecystogogue before a hepatobiliary tracer promotes visualization of the gallbladder by causing it to go through a contraction/filling cycle in gallbladder by causing it to go through a contraction/filling cycle in which the filling phase occurs during maximum exposure to the radionuclide. This maneuver can convert a false positive study that suggests the presence of acute cholecystitis to a true negative study. Other gastrointestinal interventions are aimed at enhancing the detection of gastroesophageal reflux and gastrointestinal bleeding.Many new interventions have been developed that are currently aimed at research problems rather than clinical problems. Elegant studies eliciting cortical activation in response to visual, auditory, and cognitive stimulae have been described for the brain and show clinical promise for the future. New interventions are also under investigation for the heart and kidney. The development of new tracers and instrumentation will continue to be paralleled by the development of new interventional maneuvers.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28098/1/0000545.pd