Christiane Mallett1, Matthew Latourette1, Anna Kopec2, James Luyendyk2, and Erik Shapiro1
1Radiology, Michigan State University, East Lansing, MI, United States, 2Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, United States
Synopsis
We are developing an
MRI method to measure acetaminophen toxicity in the liver. We obtained T1 maps
using the clinically approved contrast agent gadoxetate disodium (Eovist). The
contrast agent was administered by infusion to maintain a steady liver concentration
throughout the T1 mapping. Mice with acetaminophen toxicity had higher T1 and
heterogeneous gadoxetate disodium uptake compared to healthy controls. This is
a promising method for quantifying drug induced liver damage in vivo.Introduction
Acetaminophen
overdose is the most common cause of acute liver failure in North America and
Europe
1. Gadoxetate disodium (Eovist/Primovist) (Gd-EOB-DTPA) is an
FDA-approved contrast agent that is specific to hepatocytes. It is used
clinically for detection of liver cancer and cirrhosis, but has not been
applied to detect drug-induced liver injury
2. We propose to use gadoxetate
disodium uptake to measure hepatocyte health after acetaminophen toxicity. We
have developed a novel method to maintain liver enhancement during the acquisition
of T1 maps by infusing gadoxetate disodium intravenously, and applied it in
healthy mice and mice with liver damage from acetaminophen.
Methods
Imaging was performed
on a 7T Bruker BioSpec 70/30 USR using a volume transmit coil and 4-channel
receive surface coil. Mice (8-10 weeks) were anaesthetized with isoflurane then
their tail veins were catheterized. Mice were placed prone on the receive coil.
Temperature was maintained through a pad with circulating water. T1-weighted
images were acquired every minute at a resolution of 234x234x400 µm. Mice were
injected with gadoxetate disodium through the tail vein catheter during
acquisition, either with a single injection of 100 µL of gadoxetate disodium
(0.625 µmol) at a clinical dose of 0.025 mmol/kg (n=5), or with the injection
followed by an infusion of the same dose at 0.13 mL/h (0.81 µmol/h) using an
infusion pump (n=5). A series of inversion-recovery images were acquired using
the TrueFISP sequence at a resolution of 200x200x400 µm, and T1 maps were
processed using non-linear least squares parameter estimation in Matlab
3.
For acetaminophen overdose, mice were treated with 300 mg/kg acetaminophen IP
then imaged 24 h later using the injection/infusion protocol (n=2).
Results
After injection of gadoxetate
disodium in healthy mice, signal enhancement in the liver followed the expected
pattern of a steep increase followed by a slower washout phase. Time to maximum
liver enhancement was approximately 10 minutes (Figure 1). The enhancement decreased by 7-20% over the time needed to acquire a T1 map during the washout phase. When gadoxetate
disodium infusion was initiated 10 minutes after the initial bolus injection at
0.13 mL/h (0.81 µmol/h), stable signal enhancement was achieved in the liver
for over 30 minutes (Figure 2). Rectal temperature was maintained at about 29°C
(Figure 3). During the gadoxetate disodium infusion, signal enhancement in
healthy mouse liver was homogeneous, while it was heterogeneous in
acetaminophen treated livers (Figure 4). T1 of the liver in the healthy mouse
was 308 ms. In the two acetaminophen-treated mice, the liver T1 was 510 ms and
560 ms. The appearance of the T1 map is more homogeneous in the healthy mouse
than in the acetaminophen-treated mice (Figure 5). It was more difficult to
maintain a constant temperature when acquiring T1 maps than with the T1W imaging, because of RF power
deposition by the TrueFISP sequence; a modification to our temperature control
system may be necessary.
Discussion
Stable signal enhancement
of the mouse liver was achieved by using a bolus plus infusion administration
of gadoxetate disodium. This enabled the acquisition of T1 maps with consistent
amounts of gadoxetate disodium throughout the scan without washout of the
contrast agent. The gadoxetate disodium uptake pattern was different in healthy
mice and mice with liver damage from acetaminophen. T1 enhancement of the
acetaminophen damaged livers was less than that of healthy livers, indicating
that there was decreased gadoxetate disodium uptake in the damaged livers.
Conclusions
T1 maps with stable gadoxetate
disodium concentration will offer the chance to measure gadoxetate disodium
uptake and quantify hepatocyte health in drug induced liver injury and other
liver disease models. To our knowledge, this is the first description of
stable, extended gadoxetate disodium enhancement.
Acknowledgements
We thank Vickie Ruggiero for assistance with tail vein catheterization. This study is funded by the National Institutes of Health (R01 DK107697).References
1 Jaeschke, H., Xie, Y., and McGill, M.R.
(2014). Acetaminophen-induced Liver Injury: from Animal Models to Humans.
Journal of Clinical and Translational Hepatology 2, 153–161.
2 Van Beers, B.E., Pastor, C.M., and
Hussain, H.K. (2012). Primovist, Eovist: what to expect? Journal of Hepatology
57, 421–429.
3 Schmitt, P., Griswold, M.A., Jakob,
P.M., Kotas, M., Gulani, V., Flentje, M., and Haase, A. (2004). Inversion
recovery TrueFISP: Quantification ofT1,T2, and spin density. Magnetic Resonance
in Medicine 51, 661–667.