Hepatic Signal Intensity Research Articles

Use of an asialoglycoprotein receptor-targeted magnetic resonance contrast agent to study changes in receptor biology during liver regeneration and endotoxemia in rats.

The hepatic asialoglycoprotein receptor is responsible for rapid clearance of desiaylated glycoproteins from the circulation by receptor-mediated endocytosis. Previous in vitro studies in hepatocyte preparations from rats subjected to partial hepatectomy (PH) of 70% to stimulate hepatic regeneration showed decreased asialoglycoprotein (ASGP) receptor binding. We used an ASGP receptor-targeted hepatic magnetic resonance imaging (MRI) agent, BMS 180550, to demonstrate similar changes in receptor biology in vivo. BMS 180550 is an arabinogalactan-coated ultrasmall superparamagnetic iron oxide preparation. Arabinogalactan is a ligand for the ASGP receptor and, thereby, targets the contrast agent exclusively to hepatocytes. Hepatic uptake of BMS 180550 was assessed by sequential precontrast and post-contrast MRI in rats subjected to PH of 70%. In regenerating liver 1 and 3 days after PH, the maximum decrease in hepatic signal intensity (62.2% +/- 6.1 and 59.4% +/- 3.8, respectively) was significantly less than the maximum decrease seen in sham-operated animals at 1 and 3 days postsurgery (39.5% +/- 2.5 and 44% +/- 1.0, respectively). The time necessary to reach 80% of the maximum decrease in hepatic signal intensity, (t80), was less than 2 minutes in control rats and increased to 7.5 +/- 1.3 min and 11.0 +/- 2.3 minutes at 1 and 3 days post-PH, respectively. By 7 days post-PH, contrast-enhanced MRI no longer detected a difference in regenerating liver. Because BMS 180550 is taken up exclusively by the liver, clearance of the agent from the blood was used as a measure of hepatic clearance. Concentration-time curves constructed by measuring changes in blood T2 after an intravenous dose of BMS 180550 were used to determine clearance of the agent. Blood clearance of BMS 180550 in normal liver (15.4 +/- 1.08 mL/min) obeyed first-order kinetics and did not vary over the dose range tested (10 to 100 micromol/L/kg iron). One, 3, 7, and 14 days post-PH, clearance varied with dose, suggesting ASGP receptor saturation. As regeneration proceeded, the dose of contrast agent needed to cause a deviation from first-order kinetics increased, suggesting gradual recovery of ASGP receptor function. Hepatic relaxation was determined by in vitro spectroscopy 60 minutes after administration of graded doses of BMS 180550 and showed dose-dependent increases in relaxation. Kinetic analysis at 1 day post-PH demonstrated a decrease in the apparent k(m) and the maximum response, R(max), suggesting a decrease in the number of functional asialoglycoprotein receptors with concomitant increase in receptor affinity. Systemic endotoxemia, which normally accompanies hepatic regeneration induced by PH, also decreased clearance of BMS 180550 and slowed hepatic uptake of the contrast agent. Altered BMS 180550 pharmacokinetics in endotoxin-treated rats was enhanced by prior administration of small doses of competing ligand. Our studies document the value of BMS 180550 in following changes in ASGP function that accompany PH or systemic endotoxemia. This agent may be useful in assessing the degree of hepatic regeneration in patients with clinical liver disease.

Use of an asialoglycoprotein receptor-targeted magnetic resonance contrast agent to study changes in receptor biology during liver regeneration and endotoxemia in rats

The hepatic asialoglycoprotein receptor is responsible for rapid clearance of desiaylated glycoproteins from the circulation by receptor- mediated endocytosis. Previous in vitro studies in hepatocyte preparations from rats subjected to partial hepatectomy (PH) of 70% to stimulate hepatic regeneration showed decreased asialoglycoprotein (ASGP) receptor binding. We used an ASGP receptor-targeted hepatic magnetic resonance imaging (MRI) agent, BMS 180550, to demonstrate similar changes in receptor biology in vivo. BMS 180550 is an arabinogalactan-coated ultrasmall superparamagnetic iron oxide preparation. Arabinogalactan is a ligand for the ASGP receptor and, thereby, targets the contrast agent exclusively to hepatocytes. Hepatic uptake of BMS 180550 was assessed by sequential precontrast and post- contrast MRI in rats subjected to PH of 70%. In regenerating liver 1 and 3 days after PH, the maximum decrease in hepatic signal intensity (62.2% +/- 6.1 and 59.4% +/- 3.8, respectively) was significantly less than the maximum decrease seen in sham-operated animals at 1 and 3 days postsurgery (39.5% +/- 2.5 and 44% +/- 1.0, respectively). The time necessary to reach 80% of the maximum decrease in hepatic signal intensity, (t80), was less than 2 minutes in control rats and increased to 7.5 +/- 1.3 min and 11.0 +/- 2.3 minutes at 1 and 3 days post-PH, respectively. By 7 days post-PH, contrast-enhanced MRI no longer detected a difference in regenerating liver. Because BMS 180550 is taken up exclusively by the liver, clearance of the agent from the blood was used as a measure of hepatic clearance. Concentration-time curves constructed by measuring changes in blood T2 after an intravenous dose of BMS 180550 were used to determine clearance of the agent. Blood clearance of BMS 180550 in normal liver (15.4 +/- 1.08 mL/min) obeyed first-order kinetics and did not vary over the dose range tested (10 to 100 micromol/L/kg iron). One, 3, 7, and 14 days post-PH, clearance varied with dose, suggesting ASGP receptor saturation. As regeneration proceeded, the dose of contrast agent needed to cause a deviation from first-order kinetics increased, suggesting gradual recovery of ASGP receptor function. Hepatic relaxation was determined by in vitro spectroscopy 60 minutes after administration of graded doses of BMS 180550 and showed dose-dependent increases in relaxation. Kinetic analysis at 1 day post-PH demonstrated a decrease in the apparent k(m) and the maximum response, R(max), suggesting a decrease in the number of functional asialoglycoprotein receptors with concomitant increase in receptor affinity. Systemic endotoxemia, which normally accompanies hepatic regeneration induced by PH, also decreased clearance of BMS 180550 and slowed hepatic uptake of the contrast agent. Altered BMS 180550 pharmacokinetics in endotoxin- treated rats was enhanced by prior administration of small doses of competing ligand. Our studies document the value of BMS 180550 in following changes in ASGP function that accompany PH or systemic endotoxemia. This agent may be useful in assessing the degree of hepatic regeneration in patients with clinical liver disease. (Hepatology 1996 Jun;23(6):1631-41)

Superparamagnetic Iron Oxide Hepatic MR Imaging: Efficacy and Safety Using Conventional and Fast Spin‐Echo Pulse Sequences

The purpose of this study was to evaluate the technical efficacy and safety of iv ferumoxides (Feridex), a superparamagnetic iron oxide contrast agent for detection of hepatic lesions using conventional spin-echo and fast spin-echo MR images. Precontrast and postcontrast MR studies were performed on 25 patients with suspected focal hepatic lesions. Conventional T1- and T2-weighted MR images, as well as fast spin-echo and fat suppressed fast spin-echo MR images, were evaluated. Quantitative assessment of the contrast agent was performed obtaining region of interest measurements of the liver, spleen, and selected hepatic lesions. The pulse sequences were also evaluated subjectively for overall image quality and a subjective assessment of lesion detection. The use of a superparamagnetic iron oxide contrast agent led to a decrease in hepatic signal intensity on all pulse sequences. Lesion-to-liver contrast increased 41.1%, 36.5%, and 32.0% on the conventional T2, fast spin-echo, and fat suppressed fast spin echo pulse sequences, respectively. Lesion-to-liver contrast decreased on the T1-weighted postcontrast pulse sequence by 23.8%. Despite improvement in lesion-to-liver contrast, radiologists subjectively preferred the precontrast sequences because of overall better image quality. At a dose of 10 mumol/kg, ferumoxides favorably impacts lesion-to-liver contrast, and may be useful in hepatic imaging, more with conventional T2-weighted spin-echo pulse sequences than with T2-weighted fast spin-echo pulse sequence.

Pancreatic contrast enhancement with Mn-bis pyridoxal ethylene diamine diacetic acid and the influence of a hormonal stimulation of the pancreas in pigs

Pancreatic and hepatic contrast enhancement after different modes of administration of Mn-bis pyridoxal ethylene diamine diacetic acid (Mn-DPDP) and the influence of the hormones secretin and cholecystokinin on the uptake of this new contrast agent were studied by using magnetic resonance (MR) imaging and atomic absorption spectroscopy (AAS) examinations carried out on 13 young domestic pigs. Mn-DPDP was administered either as bolus injection or 30-min infusion. The course of contrast enhancement was noted. MR imaging was carried out with or without pancreatic stimulation. The Mn content in pancreatic and hepatic tissue was analyzed by using AAS. Mn-DPDP caused a significant increase (66 +/- 40.1%) in pancreatic signal intensity, an increase in hepatic signal intensity (78 +/- 23.0%), and a significantly higher Mn content on tissue samples of both organs. The results showed a wide individual range. With infusion of Mn-DPDP, pancreatic enhancement was slower, with a peak at 82 +/- 34 min compared with 54 +/- 51 min following bolus injection. The Mn content of both hepatic and pancreatic tissue determined by AAS seemed to be higher after infusion. An incomplete washout of Mn after 24 hr was demonstrated. Hormonal stimulation of the pancreas further increased pancreatic signal intensity but did not influence hepatic contrast enhancement. Infusion is the method of choice for administering Mn-DPDP because it causes an increase in hepatic signal intensity but does not change pancreatic enhancement. Although pancreatic hormonal stimulation intensifies enhancement, the increase is not statistically significant, and this practice will not contribute to day-to-day clinical practice.

MR of the kidneys, liver, and spleen in paroxysmal nocturnal hemoglobinuria.

The magnetic resonance (MR) findings in the liver, kidneys, and spleen in eight patients with paroxysmal nocturnal hemoglobinuria (PNH) were retrospectively reviewed to determine whether characteristic features could be demonstrated. Eight patients underwent abdominal MR examinations by gradient echo sequences (seven patients), spin-echo sequences (seven patients), and inversion recovery (one patient). Signal intensities of the kidneys, liver, and spleen were visually evaluated. Autopsy and liver biopsy correlation were available in one case each. Renal signal intensity was decreased in all eight patients by either gradient-echo or T2-weighted sequences and in the single inversion recovery sequence. Hepatic signal intensity was decreased in three of eight patients on spin- and gradient-echo images. Splenic signal intensity was decreased in three of eight patients on spin- and gradient-echo images, and in two of these was manifest as focal low signal spots (Gamna-Gandy bodies). While the signal intensity in the renal cortex is typically decreased in patients with PNH, signal intensities in the liver and spleen are variable. Low signal intensity in the kidneys is due to hemosiderin deposition resulting from intravascular hemolysis, whereas low signal intensity in the liver or spleen may be due to either transfusion siderosis, or as a consequence of hepatic or portal venous thrombosis.

Abdominal iron distribution in sickle cell disease: MR findings in transfusion and nontransfusion dependent patients.

Our goal was to determine the difference in iron distribution between transfusion dependent (TD) and nontransfusion dependent (NT) patients with sickle cell disease (SCD). The T2-weighted and T2*-weighted abdominal MR images in nine cases of homozygous SCD were reviewed to determine the distribution of low signal from iron in five TD and four NT patients. All eight patients with visualized spleens had decreased splenic signal intensity. One patient who had no history of splenectomy had no visualized splenic tissue. The majority of both groups had renal cortex of low signal intensity that was attributable to iron deposition from intravascular hemolysis and was not correlated with clinical renal abnormalities. None of the NT group had liver or pancreas of low signal intensity, while all five TD patients had decreased liver signal intensity and three of five had decreased pancreatic signal intensity. Decreased pancreatic signal intensity can occur in TD patients, perhaps suggesting total body iron overload. Nontransfusion dependent sickle cell patients usually have normal hepatic signal intensity and do not have total body iron overload, even in the presence of renal and splenic iron deposition.

MR imaging of hepatic iron overload in rat.

To investigate the relationship of hepatic signal intensity and T2 with histologic grading in an animal model of oral iron overload and to determine the duration of feeding necessary to produce abnormalities detectable on magnetic resonance (MR) images, hepatic iron overload was induced in 12 rats by feeding them a diet supplemented with 4% carbonyl iron for 2-11 weeks. Iron overload seen on MR images was graded independently and blindly by two radiologists as normal, mild, moderate, or severe. The rats were killed, and histologic findings were graded blindly by four pathologists using a similar subjective scale. Hepatic T2 values were estimated from spin-echo images. In the rats with iron overload, intracellular iron deposition was noted on histologic studies. On MR images, hepatic signal intensity and T2 decreased after only 2 weeks of dietary iron overload, and both continued to decrease with longer duration of feeding. There was significant correlation between iron overload duration and changes on MR images and between MR images and histologic grading (r = .92, P = .0001 for both). The mean T2 of hepatic iron overload decreased with longer duration of feeding.

Hepatic and splenic sarcoidosis: Ultrasound and MR imaging

Abdominal imaging studies may be performed for various indications in patients known to have sarcoidosis. To assess magnetic resonance imaging (MRI) and sonographic ability to detect abnormalities in sarcoidosis patients with abdominal involvement, a prospective study on 18 selected patients was performed. Besides organomegaly, when present, ultrasound demonstrated normal or increased hepatic parenchymal echogenicity, coarsening of the liver parenchyma with or without discrete nodules, focal calcifications, as well as contour irregularity. Splenic discrete nodules were seen on ultrasound in a single patient. Besides organomegaly, MRI abnormalities include abnormal hepatic signal intensity, discrete nodules, contour irregularity, speculation of small hepatic vascular branches, and a high periportal signal intensity. MRI splenic abnormalities include contour irregularity, nodularity, and abnormal signal intensity. The data presented in this study reveals the spectrum of ultrasound and MRI findings in sarcoidosis patients with abdominal organ involvement, potentially enabling the evaluation of the severity of the disease. MRI appears more sensitive than ultrasound for study of abdominal sarcoidosis.

Ethanol-induced fatty liver in the rat examined by in vivo 1H chemical shift selective magnetic resonance imaging and localized spectroscopic methods

In vivo 1H magnetic resonance imaging (MRI), chemical shift selective imaging (CSI), and localized (VOSY) 1H magnetic resonance spectroscopy (MRS) were used to study fatty infiltration in the livers of rats chronically fed an ethanol-containing all-liquid DeCarli-Lieber diet. Conventional total proton MRI showed a somewhat hyperintense liver for ethanol-fed rats, compared with pair-fed controls. CSI showed a dramatic increase in the fat signal intensity for ethanol-treated rats that was fairly homogeneous throughout the liver. However, CSI also showed a substantial decrease in the water signal intensity for the ethanol-treated rats compared to pair-fed control rats. 1H VOSY MR spectra also showed a 5.5-fold increase in the methylene resonance (1.3 ppm) of fat and a 50–70% decrease in the water resonance (4.8 ppm). Relative in vivo proton T 1 and T 2 relaxation times for the water resonance separate from the fat resonance, determined from modified VOSY experiments, were found to tend to increase and decrease, respectively, for ethanol-treated rat livers compared with controls. The decrease in hepatic water signal intensity could be accounted for by the decrease in T 2 and decrease in water density due to the presence of accumulated hepatic fat (∼250 mg/g wet weight of liver). When ethanol was withdrawn from the chronically treated rats, fatty infiltration was observed by both CSI and VOSY spectra to revert toward control values with a half-life of 2–4 days. By day 16, however, the signal intensity for hepatic fat was still significantly higher than control levels. In vitro 1H MRS studies of chloroform-methanol extracts confirmed the 5.5-fold increase in total hepatic fat induced by the chronic ethanol treatment, and showed further that triacylglycerols were increased 7.7-fold, cholesterol was increased fourfold, and phospholipids were increased 3.3-fold, compared with liver extracts from pair-fed control rats.