1. Changes in the Brain after Liver Transplantation: An Analysis on T1-weighted MR Imaging Kotake T, Ishimaru H, Yasui K, Morikawa M, Ideguchi R, Enokizono M, and Uetani M. Nagasaki University, Depertment of Radiology, Nagasaki Japan

2. Background A variety of MR imaging findings are associated with liver cirrhosis with or without hepatic encephalopathy (HE), and most of these are reversible after liver transplant (LT). T1-hyperintense globus pallidus (GP) is common abnormality and is reversible when liver function returns to normal; however, signal changes in other areas are not well understood. Pujol A, et al. Hyperintense globus pallidus on T1-weighted MRI in cirrhotic patients is associated with severity of liver failure. Neurology 1993;43:65-69

3. Are the signal changes limited to GP? Before LTAfter LT

4. MR imaging features in patients with cirrhosis w/ or w/o overt HE T1WI1H-MRSMTRT2/FLAIRDWI MR imaging abnormalities Symmetric high signal of the GP and SN Increase in Glx; depletion of Myol; decrease in Cho; normal NAA Mild and diffuse decrease in WM WM high signal intensities involving predominantly the corticospinal tract; focal high-signal T2 lesions in subcortical WM Increase mean diffusivity in WM; Normal FA Functional consequences Parkinsonism (particularly if SN is involved) Overt hepatic encephalopathy (particularly with increase in Glx) Functional abnormalities of the corticospinal tract Functional abnormalities of the corticospinal tract; cognitive impairment Cognitive impairment Rovira A. MR imaging findings in hepatic encephalopathy. 2008 ???

5. Purpose The purpose of this study was to elucidate T1WI abnormalities associated with cirrhosis by comparing before and after successful LT, and to investigate the relationship between the abnormalities and clinical consequences.

6. Materials & Methods 33 male and 26 female cirrhotic patients (57 ± 10 years) were included (14 with clinical HE). Spin echo T1WI (TR/TE=350/13, 5 mm thickness with a 1 mm gap) was obtained using 3T MR scanner with an 8 channel head coil (Excite HD, GE) before and after successful LT from 58 cirrhotic patients (14 with clinical HE). Signal intensity ratios (SIR) of the white matter (WM), putamen, GP, and thalamus relative to the frontal cortex before and after LT were compared using paired t-test.

7. Signal intensity ratio (SIR) relative to frontal cortex

8. Materials & Methods A blinded radiologist graded portosystemic shunts (PS) score on abdominal CT or MRI using a scale system proposed by Yoshikawa et al. Yoshikawa T, Mitchell DG. MR evaluation of portal hypertensive collateral shunting vessels for predicting outcome after transjugular intrahepatic portosystemic shunt. Magn Reson Med Sci 2011; 10:21-7 The stepwise multiple linear regression analysis of PS score, serum bilirubin, albumin, prothrombin time, and NH3, for the effect on each SIR was performed. Multivariate logistic regression analysis involving stepwise selection was used to determine predictors of HE.

9. Results: SIR changes after LT SIR of the GP, putamen, and WM, significantly decreased after liver transplantation (paired t-test<0.01), although that of the thalamus showed no significant change. GP Putamen WM Thalamus Before After

10. The correlation coefficient for SIRs and Clinical Markers before LT IndexesWM/C Putamen/ CGP/C Thalamus/ CPS scoreBilAlbPTNH3 WM/C1 0.760.750.54 0.07-0.20-0.060.080.2 Putamen/C 0.76 1 0.900.73 0.10-0.22-0.160.090.29 GP/C 0.750.90 1 0.62 0.16-0.17-0.25-0.030.30 Thalamus/ C 0.540.730.62 1-0.04-0.14-0.090.220.11 PS score0.070.100.16-0.0410.01-0.11-0.300.14 Bil-0.20-0.22-0.17-0.140.011-0.11-0.46-0.35 Alb-0.06-0.16-0.25-0.09-0.11 10.21-0.33 PT0.080.09-0.030.22-0.30-0.460.211-0.01 NH30.220.290.300.110.14-0.35-0.33-0.011 The SIRs correlated moderately to strongly with each other.

11. Correlations of each SIR and Clinical Markers before LT Markersbefore LT GP / CPutamen / CWM / CThalamus / C P valuer valueP valuer valueP valuer valueP valuer value NH3 0.07 0.03*0.29 0.100.39 Bil 0.370.330.310.73 Alb 0.200.600.900.28 PT (%) 0.920.500.540.09 PS score 0.390.640.770.85 *The stepwise multiple linear regression analysis revealed that NH3 was only the factor significantly correlated with SIR of putamen (P=0.03).

12. Scatterplots of Putamen/C and NH3 NH3 Putamen/Cortex P=0.03 r=0.29

13. Logistic Regression Analysis to Determine Predictors of HE VariablesAdjusted Odds RatioP Value WM / Cortex0.820.37 Putamen / Cortex2x10 -3 0.96 GP / Cortex4x10 -3 0.95 Thalamus / Cortex0.390.53 PS score0.150.70 Bil0.620.43 Alb0.020.89 PT0.300.58 NH3 6.190.01

14. Results SIR of the WM, putamen, and GP significantly decreased after liver transplantation (paired t-test<0.01), although that of the thalamus showed no significant change. The SIRs correlated moderately to strongly with each other. The stepwise multiple linear regression analysis revealed that NH3 was only the factor significantly correlated with SIR of putamen before LT. The stepwise logistic regression analysis revealed that NH3 before LT was only the factor significantly correlated with HE.

15. Discussion: Basal Ganglia Although it is broadly accepted that the agent responsible for relaxation time shortening in the basal ganglia is manganese, a contribution of other paramagnetic compounds cannot be excluded. Herynek et al. speculated that ferritin is another potential contributor to the relaxation time shortening in the putamen : T2 shortening in the putamen did not reach the control values even 15 years after LT. Herynek V, Wagnerova D, Hejlova I, Dezortova M, Hajek M. Changes in the brain during long-term follow-up after liver t ransplantation. Journal of magnetic resonance imaging : JMRI 2012

16. Discussion: WM Herynek et al. also showed T1 shortening in WM, whereas no significant T2 shortening. This finding indicated some structural changes in the WM other than paramagnetic compound. Herynek V, Wagnerova D, Hejlova I, Dezortova M, Hajek M. Changes in the brain during long-term follow-up after liver transplantation. Journal of magnetic resonance imaging : JMRI 2012 Increased WM volume was found in patients with higher PS scores, which can be attributed to the development of low-grade brain edema. Zhang LJ, Qi R, Zhong J, Xu Q, Zheng G, Lu GM. The effect of hepatic encephalopathy, hepatic failure, and portosystemic shunt on brain volume of cirrhotic patients: a voxel-based morphometry study. PloS one 2012 MTR↓ in nonalcoholic cirrhosis and ADC↑ with increasing HE severity Miese F, Kircheis G, Wittsack HJ, et al. 1H-MR spectroscopy, magnetization transfer, and diffusion-weighted imaging in alcoholic and nonalcoholic patients with cirrhosis with hepatic encephalopathy. AJNR 2006

17. Multiple factors may affect SIRs Some structural change ferritin manganese edema T1 shortening T1 elongation

18. Limitation Analyses on T1WI only T1 relaxation maps were not calculated. The interval between MR before and after LT ranged between 1 year to 7 years. Many other clinical markers were not analyzed.

19. Conclusion SIR of the WM, putamen, and GP significantly decreased after successful LT, and the signal increases of the WM, putamen, and GP were considered to indicate reversible abnormalities associated with cirrhosis. We could not find out the correlation of signal increases in these areas to any clinical consequences. Before LTAfter LT

21. Discussion: GP (& SN) Bilateral symmetric increased T1 signal intensity at the globus pallidus and substantia nigra due to manganese concentration Normalization of MR imaging signal intensity abnormalities and manganese levels after liver transplantation

22. Discussion: Putamen T1 relaxation time were significantly lower than the control possibly doe to higher concentration of iron storage proteins (= ferritin) Herynek V, Wagnerova D, Hejlova I, Dezortova M, Hajek M. Changes in the brain during long-term follow-up after liver transplantation. Journal of magnetic resonance imaging : JMRI 2012

25. The correlations between the expression of the hepatic transporters and the MR imaging parameters are shown in the Table. The multiple linear regression analysis including all enhancement and pharmacokinetic parameters identified HEF as the only parameter significantly related to Oatp1a1 and Mrp2 expression ( P,.001, r = 0.74 and P,.001, r = 0.70, respectively).

26. With multivariate analysis, only infection during stage I-II HE, leukocytosis, and thrombocytopenia at admission were significantly correlated with progression of HE at the 5% level in the stepwise logistic regression models: demonstrable infection during stage I-II HE (OR: 6.16 [95% CI: 2.14, 19.31], P 0.01); increase in WBC count by 2 109/L (OR: 1.43 [95% CI: 1.19, 1.77], P 0.01); decrease in platelet count by 20 109/L (OR: 1.24 [95% CI: 1.05, 1.51], P 0.05).

27. Correlations of SIRs between Clinical Markers after LT Markersbefore LT GP / CPutamen / CWM / CThalamus / C P valuer valueP valuer valueP valuer valueP valuer value NH3 0.250.990.590.63 Bil 0.990.230.490.69 Alb 0.04*-0.350.03*-0.320.02*-0.31 0.31 PT (%) 0.960.84 0.900.85 PS score 0.36 0.05 0.320.30 *The stepwise multiple linear regression analysis revealed that Alb was the factor significantly correlated with SIR of GP (P<0.01), putamen (P=0.01), and WM (P=0.02).