MRI Evaluation of Acetaminophen Induced Liver Failure in Mice using T1 Mapping and Stable Gadoxetate Disodium Administration
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 Europe1. 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 injury2. 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 Matlab3. 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.

Figures

Enhancement over baseline after injection of 100 uL of gadoxetate disodium. Baseline signal was calculated over at least 5 scans pre-injection. Liver signal is the average of 4 coronal slices covering the ventral to middle part of the liver. ROIs were drawn to cover the entire liver in each slice.

Stable liver enhancement with gadoxetate disodium infusion. Each point is the average of 4 slices from one mouse liver; error bars are the standard deviation of the four slices. Mice were maintained at 29°C and infused with gadoxetate disodium after a bolus injection.

Liver signal and mouse temperature were well-controled during image acquisition. Signal stability is the standard deviation of the liver signal over 20 minutes after infusion started. Temperature was measured over 35 minutes following the initial bolus injection of 100 µL.

Liver enhancement during gadoxetate disodium infusion in healthy and acetaminophen-treated mice. Coronal slices at baseline (top row) and during the steady enhancement stage of gadoxetate disodium infusion (bottom row). Two healthy mice and two acetaminophen-treated mice are shown. Scale bar is 0.5 cm.

T1 maps of mouse liver acquired during the stable enhancement stage of gadoxetate disodium infusion for a healthy mouse (A) and two acetaminophen-treated mice (B,C). T1 is homogeneous for the healthy mouse but heterogeneous for the acetaminophen-treated mice.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
3851