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(Radiology. 2000;216:683-691.)
© RSNA, 2000

Neuroradiology

MR Imaging and 1H Spectroscopy of Brain Metabolites in Hepatic Encephalopathy: Time-Course of Renormalization after Liver Transplantation1

Thomas Naegele, MD, Wolfgang Grodd, MD, Richard Viebahn, MD, Uwe Seeger, PhD, Uwe Klose, PhD, Dietmar Seitz, MD, Stephan Kaiser, MD, Irina Mader, MD, Jochen Mayer, MD, Werner Lauchart, MD, Michael Gregor, MD and Karsten Voigt, MD

1 From the Depts of Neuroradiology (T.N., W.G., U.S., U.K., D.S., I.M., J.M., K.V.), General Surgery (R.V., W.L.), and Gastroenterology and Hepatology (S.K., M.G.), Univ of Tübingen, Hoppe-Seyler Str. 3, 72076 Tübingen, Germany. Received Apr 26, 1999; revision requested Jul 12; final revision received Jan 24, 2000; accepted Mar 7. Supported in part by the Deutsche Forschungsgemeinschaft (DFG: KL 1093/1-1). U.K. supported by a grant from the Federal Ministry of Education Science, Research and Technology (Foe. 01KS9602). T.N. supported by the Interdisciplinary Clinical Research Center (IKFZ), Tübingen. Address correspondence to T.N. (e-mail: thomas.naegele@med.uni-tuebingen.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate changes in hydrogen 1 magnetic resonance (MR) spectroscopic findings in overt or subclinical hepatic encephalopathy (HE) after liver transplantation and to compare these changes with clinical outcomes and basal ganglia high signal intensity (BGH).

MATERIALS AND METHODS: Twenty-two patients scheduled for liver transplantation and 17 healthy control subjects were examined with 1H MR spectroscopy and standard nonenhanced MR imaging. Eight patients underwent complete MR imaging and 1H spectroscopic examinations before liver transplantation and at 3–4-week, 12–28-week, and 10–12-month follow-up after liver transplantation.

RESULTS: Before liver transplantation, typical 1H spectroscopic changes—decreased myo-inositol (mI)/creatine (Cr) and choline (Cho)/Cr ratios and an elevated glutamine and glutamate (Glx)/Cr ratio—were found in 21 patients. Eighteen patients had BGH at T1-weighted imaging. Three to 7 months after liver transplantation, the mI/Cr and Glx/Cr ratios were within the normal range in five of eight and eight of eight patients, respectively, without any residual signs of subclinical or overt HE; however, at MR imaging, seven patients still had BGH.

CONCLUSION: After successful liver transplantation, renormalization of HE-specific brain metabolite changes is detected at 1H spectroscopy and precedes the disappearance of BGH. The neuropsychologic signs of subclinical or overt HE follow the changes seen at 1H spectroscopy rather than those seen at MR imaging.

Index terms: Brain, diseases, 10.59, 10.891 • Brain, metabolism • Brain, MR, 10.121411, 10.121416, 10.12145 • Liver, cirrhosis, 761.79 • Liver transplantation, 761.45, 761.79 • Magnetic resonance (MR), spectroscopy, 10.12145, 18.12145


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Hepatic encephalopathy (HE) is a cerebral disorder associated with neuropsychologic dysfunctions that frequently occur in patients with chronic liver disease (1–3). The neuropsychologic impairments of HE range from mild deficits in psychomotor abilities to confusion and finally stupor in higher grades.

In routine clinical practice, HE is commonly diagnosed at the patient’s bedside, and it is often underestimated by physicians because the verbal abilities of the patients are often well preserved (4). To detect lower grades of HE, neuropsychologic examinations are necessary (5,6). However, poor specificity for the detection of HE and the influences of age, sex, and intellectual ability (7) are drawbacks of these examinations.

Recently, it has been shown that in patients with HE, a specific pattern at localized proton (ie, hydrogen 1) MR spectroscopy of the brain exists when short echo times are used. 1H MR spectroscopy is a noninvasive method that allows the detection and quantification of various brain metabolites (2,3,8,9). The results of spectroscopic examinations of gray and white matter in patients with HE or subclinical HE characteristically reveal decreased amplitudes of myo-inositol (mI) and choline (Cho) combined with increased levels of glutamine and glutamate (Glx) (Fig 1). In comparisons of the spectroscopic results of neuropsychiatric examinations, it has been found that HE and subclinical HE can be detected reliably and reproducibly by using 1H MR spectroscopy, with a sensitivity of more than 90% (8–11).



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  		Figure 1a. MR imaging and MR spectroscopic findings in (a-c) a patient with liver cirrhosis and overt HE and (d-f) a healthy control subject. (a, d) On the transverse T1-weighted images (repetition time msec/echo time msec, 580/12), the basal ganglia (arrows) in the patient (a) has pronounced high signal intensity compared with that in the control subject (d). The box in a outlines the volume of interest for MR spectroscopic analysis. (b, e) On the corresponding transverse T2-weighted images (3,000/90), there are no relevant signal intensity changes. (c, f) MR spectroscopic measurements in the patient (c) reveal a characteristic increase in Glx/phosphocreatine (PCr) ratio and decrease in mI/PCr and Cho/phosphocreatine ratios compared with these ratios in the control subject (f). NAA = N-acetylaspartate.

 


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  		Figure 1b. MR imaging and MR spectroscopic findings in (a-c) a patient with liver cirrhosis and overt HE and (d-f) a healthy control subject. (a, d) On the transverse T1-weighted images (repetition time msec/echo time msec, 580/12), the basal ganglia (arrows) in the patient (a) has pronounced high signal intensity compared with that in the control subject (d). The box in a outlines the volume of interest for MR spectroscopic analysis. (b, e) On the corresponding transverse T2-weighted images (3,000/90), there are no relevant signal intensity changes. (c, f) MR spectroscopic measurements in the patient (c) reveal a characteristic increase in Glx/phosphocreatine (PCr) ratio and decrease in mI/PCr and Cho/phosphocreatine ratios compared with these ratios in the control subject (f). NAA = N-acetylaspartate.

 


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  		Figure 1c. MR imaging and MR spectroscopic findings in (a-c) a patient with liver cirrhosis and overt HE and (d-f) a healthy control subject. (a, d) On the transverse T1-weighted images (repetition time msec/echo time msec, 580/12), the basal ganglia (arrows) in the patient (a) has pronounced high signal intensity compared with that in the control subject (d). The box in a outlines the volume of interest for MR spectroscopic analysis. (b, e) On the corresponding transverse T2-weighted images (3,000/90), there are no relevant signal intensity changes. (c, f) MR spectroscopic measurements in the patient (c) reveal a characteristic increase in Glx/phosphocreatine (PCr) ratio and decrease in mI/PCr and Cho/phosphocreatine ratios compared with these ratios in the control subject (f). NAA = N-acetylaspartate.

 


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  		Figure 1d. MR imaging and MR spectroscopic findings in (a-c) a patient with liver cirrhosis and overt HE and (d-f) a healthy control subject. (a, d) On the transverse T1-weighted images (repetition time msec/echo time msec, 580/12), the basal ganglia (arrows) in the patient (a) has pronounced high signal intensity compared with that in the control subject (d). The box in a outlines the volume of interest for MR spectroscopic analysis. (b, e) On the corresponding transverse T2-weighted images (3,000/90), there are no relevant signal intensity changes. (c, f) MR spectroscopic measurements in the patient (c) reveal a characteristic increase in Glx/phosphocreatine (PCr) ratio and decrease in mI/PCr and Cho/phosphocreatine ratios compared with these ratios in the control subject (f). NAA = N-acetylaspartate.

 


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  		Figure 1e. MR imaging and MR spectroscopic findings in (a-c) a patient with liver cirrhosis and overt HE and (d-f) a healthy control subject. (a, d) On the transverse T1-weighted images (repetition time msec/echo time msec, 580/12), the basal ganglia (arrows) in the patient (a) has pronounced high signal intensity compared with that in the control subject (d). The box in a outlines the volume of interest for MR spectroscopic analysis. (b, e) On the corresponding transverse T2-weighted images (3,000/90), there are no relevant signal intensity changes. (c, f) MR spectroscopic measurements in the patient (c) reveal a characteristic increase in Glx/phosphocreatine (PCr) ratio and decrease in mI/PCr and Cho/phosphocreatine ratios compared with these ratios in the control subject (f). NAA = N-acetylaspartate.

 


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  		Figure 1f. MR imaging and MR spectroscopic findings in (a-c) a patient with liver cirrhosis and overt HE and (d-f) a healthy control subject. (a, d) On the transverse T1-weighted images (repetition time msec/echo time msec, 580/12), the basal ganglia (arrows) in the patient (a) has pronounced high signal intensity compared with that in the control subject (d). The box in a outlines the volume of interest for MR spectroscopic analysis. (b, e) On the corresponding transverse T2-weighted images (3,000/90), there are no relevant signal intensity changes. (c, f) MR spectroscopic measurements in the patient (c) reveal a characteristic increase in Glx/phosphocreatine (PCr) ratio and decrease in mI/PCr and Cho/phosphocreatine ratios compared with these ratios in the control subject (f). NAA = N-acetylaspartate.

 
Preliminary data indicate that liver transplantation may completely reverse the spectral abnormalities in HE and subclinical HE (12). In this study, we focused our investigation on the time-course of changes in spectroscopic findings after liver transplantation, inasmuch as characteristic changes of brain metabolites can be detected even in the mildest forms of subclinical HE or HE (8,13–15). These changes were compared with the clinical outcomes and the development of basal ganglia high signal intensity (BGH).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Twenty-two consecutive patients (15 men, seven women; mean age ± SD, 40 years ± 11; age range, 22–57 years) scheduled for liver transplantation in our transplantation surgery department were examined with MR imaging and 1H MR spectroscopy in the same session. Seventeen healthy volunteers (mean age ± SD, 28 years ± 5; age range, 22–37 years) who underwent the same examinations served as control subjects. All of the patients and volunteers gave written informed consent for the study. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. This combined patient and volunteer study was approved by our local medical ethics committee.

Eight of the 22 patients scheduled for liver transplantation underwent MR spectroscopy examinations before liver transplantation and follow-up examinations 3–4 weeks, 12–28 weeks, and 10–12 months after liver transplantation. The selection of these intervals was based on the experiences of three preliminary examinations performed for 6 months, in which 3–4 weeks turned out to be the shortest tolerable interval after surgery and 3–6 months, the interval at which decisive MR spectroscopic changes occurred. The 10–12-month interval was chosen for the long-term follow-up after liver transplantation to determine whether posttransplantation changes are stable. The causes of liver dysfunction in the 22 patients were hepatitis B or C in five patients, autoimmune hepatitis in two, primary sclerosing cholangitis in two, Wilson disease in two, biliary cirrhosis in two, alcohol-related cirrhosis in eight, and acute liver failure of unknown genesis in one. Two of the 22 patients had Child-Pugh class B cirrhosis, and 20 of them had Child-Pugh class C disease (Table).


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  		Patient and Control Subject Data
 
1H MR Spectroscopy and MR Imaging
1H MR spectroscopy and MR imaging were performed by using a 1.5-T whole-body tomograph (Magnetom Vision; Siemens, Erlangen, Germany) with actively shielded gradients (25 mT/m, 600 µsec linear ramp time) and a commercially available circularly polarized head coil. For the follow-up examinations, exact reproducibility of the spectral localization was of special importance. This was achieved by acquiring three orthogonal (sagittal, transverse, and coronal) gapless, heavily T2-weighted (turbo factor, 15), turbo spin-echo data sets within 2 minutes for three-dimensional positioning of the volume of interest.

Because it has been shown that occipital gray and white matter and parietal white matter regions exhibit essentially identical MR spectroscopic metabolite changes in HE (8,12), we decided to place the volume of interest in the medial part of the occipital lobe. This area contains gray and white matter and allows measurement of a 2 x 3 x 2-cm3 volume of interest with good homogeneity of the magnetic field (Fig 1).

For the detection and quantification of mI and Glx, it is essential to use spectroscopic sequences with a short echo time to minimize the influence of J coupling and T2 relaxation, because both of these factors lead to a signal intensity decrease. In former 1H MR spectroscopic studies (3,8,9,16), an echo time of 20–30 msec was commonly applied. In this study, we used a self-designed earlier described stimulated echo acquisition mode sequence that was optimized for a very short echo time of 5 msec by exploiting the full available gradient field strength of 25 mT/m and the shortest ramp time of 600 µsec to spoil undesired outer volume signals (17).

Suppression of the dominant water signal was performed by using three preceding Gaussian pulses (60-Hz bandwidth). The mixing time of the stimulated echo acquisition mode sequence was 5 msec, and the repetition time used was 1,500 milliseconds. These parameters accounted for a total measurement time of 3 minutes for 128 acquisitions.

Spectral postprocessing consisted of 4-K zero filling, 3-Hz Gaussian apodization for noise reduction, a low-frequency filtering of the free induction decay for additional water suppression (3), fast Fourier transformation, and zero- and first-order phase correction. Additional eddy current correction (18), although not mandatory in most cases because of the actively shielded gradient system, was performed and resulted in slightly further improved spectra in a few examinations. After baseline correction, Gaussian line shapes were used in a standard line-fitting procedure of the frequency domain to approximate the signal intensities of mI (3.56 ppm), scyllo-inositol (3.35 ppm), {alpha}-Glx (3.77 ppm), creatine (Cr, 3.03 ppm), Cho (3.22 ppm), ß, {gamma}-Glx (2.05–2.45 ppm), and N-acetylaspartate (2.0 ppm).

In the range of {alpha}-Glx resonances, a peak overlap of Glx with other underlying resonances exists. In previous studies, in which a plain peak integration of 3.72–3.82 ppm has been used to evaluate {alpha}-Glx levels (2), it has been found that the integrated signal intensity corresponds well to the predominant glutamine signal intensity. Instead of peak integration, we used a variable triplet (free amplitude of the two outer lines) with a coupling constant J of approximately 6 Hz (estimation from phantom measurements) for the approximation of {alpha}-Glx signal intensities in the line-fitting procedure. The good quality of the line fit approximation is demonstrated in Figure 2. After line fitting, peak integral ratios were calculated for mI, {alpha}-Glx, and Cho levels relative to the Cr level, as proposed by Kreis et al (2) and Ross et al (8,9). For interindividual comparison, these ratios in the patients and in the control group were averaged. The time-course of these metabolite changes during the different follow-up intervals—that is, 3–4 weeks, 12–28 weeks, and 10–12 months after liver transplantation—were determined in eight patients.



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  		Figure 2. Graph illustrates the quality of the line fit. The difference between the measured spectrum (dotted line) and the fit (solid line) is demonstrated. NAA = N-acetylaspartate, PCr = phosphocreatine.

 
MR imaging consisted of transverse nonenhanced T1-weighted spin-echo and T2-weighted turbo spin-echo sequences. The imaging parameters were 580/12 (repetition time msec/echo time msec) and a 2-minute acquisition time for T1-weighted imaging and 3,000/90 and a 3-minute acquisition time for T2-weighted imaging. The section thickness was 5 mm with an intersection gap of 1 mm.

In chronic liver disease, the areas of BGH on T1-weighted images are most pronounced in the globus pallidus (19–21). Because the reversibility of BGH after liver transplantation has been shown in several studies (11,22,23), we evaluated also the signal intensity of the globus pallidus on T1-weighted images. For this purpose, the signal intensities of the globus pallidus and frontal white matter were measured and the ratios were calculated in all the patients and control subjects. The reversibility and time-course of BGH changes after liver transplantation were compared with the changes in metabolites at MR spectroscopy.

Brain atrophy was evaluated qualitatively by two experienced neuroradiologists (T.N., W.G.), who analyzed, by means of consensus, the widths of the supratentorial and infratentorial external and internal cerebrospinal fluid spaces in relation to the ages of the patients.

Clinical Outcome
Clinical examinations to grade the HE, including a number connection test (24), were performed by the referring hepatologist immediately before or after the MR examinations. The patients were classified as having either HE or subclinical HE without subspecification, or as having no evidence of HE or subclinical HE. This simple classification was chosen as in a former detailed examination of 20 patients with liver cirrhosis (8,25). The value of MR spectroscopy in the objective detection of subclinical HE and low-grade HE could be demonstrated, whereas it was not possible to discriminate subclinical HE and low-grade HE by using MR spectroscopy alone. Evidence of subclinical HE or HE was assumed if either clinical symptoms such as disturbed consciousness, personality changes, intellectual deterioration, or asterixis were detected, or the patient’s number connection test score was pathologic. The number connection test score was classified as normal as long as the time to finish the test was less than 10 times the subject’s age in decades (26).

Another reason that we followed this simple classification system in determining whether patients had no evidence of HE or had HE or subclinical HE without further subspecification, as proposed by Parsons-Smith (subclinical HE = grade 0, HE = grade 1–4) (26), was that this system was sufficient for our main interest, which was the time-course of the renormalization of brain metabolite changes after liver transplantation compared with clinical outcomes and the BGH on T1-weighted images.

Statistical Evaluation
The metabolite ratios in the control subjects and in 21 of the 22 patients with subclinical HE or HE were analyzed for Gaussian distribution before testing for the significant differences between the two groups with the one-sided two-sample Student t test. For comparison of the clinical and MR spectroscopic data, we exploited the results of Ross et al (8), who elaborated quantitative criteria that enable a prediction of subclinical HE and HE with MR spectroscopic data. They judged subclinical HE or HE to be present when the mI/Cr and Cho/Cr ratios were less than 2 SDs below normal, with or without a Glx/Cr ratio more than 1 SD above normal. In the first step of this analysis, we investigated whether the mean values of the metabolite ratios in the patients with HE or subclinical HE fulfilled the criteria of Ross et al. Furthermore, we applied these criteria in each of the follow-up examinations.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Before Liver Transplantation
According to clinical examination and psychometric test results, 21 of the 22 patients had HE or subclinical HE, whereas one patient with acute liver failure had no evidence of HE. The brain metabolite ratios in the 21 patients with subclinical HE or HE and in the 17 control subjects had clear differences (Fig 3). The mean mI/Cr ratio (± SD) in the patients was 0.34 ± 0.1, which was more than 2 SDs below the mean mI/Cr ratio in the healthy volunteers, 0.65 ± 0.06 (Student t test, P < .001). Similar results were observed for the mean Cho/Cr ratio: 0.4 ± 0.06 in the patients and 0.59 ± 0.06 in the volunteers (Student t test, P < .001). Only the difference in mean Glx/Cr ratio between the patients (1.08 ± 0.15) and the volunteers (0.89 ± 0.1) was smaller, with an overlap of the SDs (Student t test, P < .005) (Fig 3).



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  		Figure 3. Graph depicts the comparison of metabolite ratios in the control and patient groups before liver transplantation. The patients have a significantly decreased mI/Cr ratio (P < .001) and Cho/Cr ratio (P < .001) and an elevated Glx/Cr ratio (P < .005). SHE = subclinical HE.

 
Thus, the findings in the 21 patients with HE or subclinical HE statistically confirmed the criteria of Ross et al (8) for predicting HE or subclinical HE with MR spectroscopic data. In particular, these criteria were not fulfilled in a single control subject or in the patient with acute liver failure, who did not present with spectral or clinical HE–specific abnormalities before liver transplantation (Fig 4).



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  		Figure 4a. Graphs depict the time-course of MR spectroscopic metabolite ratios of (a) Glx/Cr, (b) mI/Cr, and (c) Cho/Cr in eight patients before and after liver transplantation. Each symbol ({lozenge}, {blacklozenge}, {triangleup}, {blacktriangleup}, {circ}, •, {blacksquare}, x) represents one patient. Mean values in the healthy control (- - -) and patient (- · -) groups (including patients before liver transplantation and patients who did not undergo transplantation) and the SDs (arrows) are inserted for comparison. There is almost complete renormalization of Glx/Cr, mI/Cr, and Cho/Cr ratios 3-7 months after liver transplantation, as indicated by the convergence of almost all of the values into the control group range. One year after transplantation, the patient with chronic rejection ({blacklozenge}) had slight persisting elevations in the Glx/Cr ratio (a), but a normal mI/Cr ratio (b). No abnormalities were found in the one case of acute liver failure with no evidence for HE (•).

 


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  		Figure 4b. Graphs depict the time-course of MR spectroscopic metabolite ratios of (a) Glx/Cr, (b) mI/Cr, and (c) Cho/Cr in eight patients before and after liver transplantation. Each symbol ({lozenge}, {blacklozenge}, {triangleup}, {blacktriangleup}, {circ}, •, {blacksquare}, x) represents one patient. Mean values in the healthy control (- - -) and patient (- · -) groups (including patients before liver transplantation and patients who did not undergo transplantation) and the SDs (arrows) are inserted for comparison. There is almost complete renormalization of Glx/Cr, mI/Cr, and Cho/Cr ratios 3-7 months after liver transplantation, as indicated by the convergence of almost all of the values into the control group range. One year after transplantation, the patient with chronic rejection ({blacklozenge}) had slight persisting elevations in the Glx/Cr ratio (a), but a normal mI/Cr ratio (b). No abnormalities were found in the one case of acute liver failure with no evidence for HE (•).

 


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  		Figure 4c. Graphs depict the time-course of MR spectroscopic metabolite ratios of (a) Glx/Cr, (b) mI/Cr, and (c) Cho/Cr in eight patients before and after liver transplantation. Each symbol ({lozenge}, {blacklozenge}, {triangleup}, {blacktriangleup}, {circ}, •, {blacksquare}, x) represents one patient. Mean values in the healthy control (- - -) and patient (- · -) groups (including patients before liver transplantation and patients who did not undergo transplantation) and the SDs (arrows) are inserted for comparison. There is almost complete renormalization of Glx/Cr, mI/Cr, and Cho/Cr ratios 3-7 months after liver transplantation, as indicated by the convergence of almost all of the values into the control group range. One year after transplantation, the patient with chronic rejection ({blacklozenge}) had slight persisting elevations in the Glx/Cr ratio (a), but a normal mI/Cr ratio (b). No abnormalities were found in the one case of acute liver failure with no evidence for HE (•).

 
The MR imaging findings in 18 of the 22 patients revealed typical bilateral areas of BGH, which were most pronounced in the globus pallidus on T1-weighted spin-echo images, as described by other groups (19–21). In addition, global brain atrophy was found in seven of the eight patients with alcohol-related liver dysfunction.

Before liver transplantation (Figs 4, 5), the Glx/Cr, mI/Cr, and Cho/Cr ratios in seven of the eight patients who underwent MR spectroscopy and MR imaging follow-up were pathologically changed. BGH was found in all cases. Clinical examination and number connection test results revealed signs of HE or subclinical HE in seven of the eight patients. All seven of these patients fulfilled the MR spectroscopic criteria for subclinical HE or HE defined by Ross et al (8) (Fig 4).



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  		Figure 5a. (a) Graphs depict the time-course of globus pallidus/white matter (gp/wm) signal intensity ratios on T1-weighted images after liver transplantation (LTx). Each symbol ({lozenge}, {blacklozenge}, {triangleup}, {blacktriangleup}, {circ}, •, {blacksquare}, x) represents one patient. Mean values (- - -) in the healthy control and patient groups (including patients before liver transplantation and patients who did not undergo transplantation) and the SDs (arrows) are inserted for comparison. In contrast to the MR spectroscopic findings, the MR images revealed longer-lasting areas of BGH, with elevated signal intensity levels in seven of eight patients 7 months after LTx. Note the remaining area of high signal intensity in the case of chronic rejection ({blacklozenge}). (b) The clinical outcome of liver transplantation (LTx) was concordant with the MR spectroscopic results: 3-7 months after LTx, all eight patients were clinically and psychometrically free of subclinical or overt HE (SHE/HE).

 


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  		Figure 5b. (a) Graphs depict the time-course of globus pallidus/white matter (gp/wm) signal intensity ratios on T1-weighted images after liver transplantation (LTx). Each symbol ({lozenge}, {blacklozenge}, {triangleup}, {blacktriangleup}, {circ}, •, {blacksquare}, x) represents one patient. Mean values (- - -) in the healthy control and patient groups (including patients before liver transplantation and patients who did not undergo transplantation) and the SDs (arrows) are inserted for comparison. In contrast to the MR spectroscopic findings, the MR images revealed longer-lasting areas of BGH, with elevated signal intensity levels in seven of eight patients 7 months after LTx. Note the remaining area of high signal intensity in the case of chronic rejection ({blacklozenge}). (b) The clinical outcome of liver transplantation (LTx) was concordant with the MR spectroscopic results: 3-7 months after LTx, all eight patients were clinically and psychometrically free of subclinical or overt HE (SHE/HE).

 
Post–Liver Transplantation Findings
Three to 4 weeks after liver transplantation (Figs 4–6), the Glx/Cr ratio began to decrease in all eight patients, but pathologic values were still present in six of the eight patients. Furthermore, after 4 weeks, the mI/Cr ratio showed a marked increase in six of eight patients and the values approached those in the healthy control patients (Fig 4). Although the Cho/Cr ratio remained slightly below normal in two of the eight patients, there was early renormalization in three of the eight patients, in whom the changed ratio was within the normal range, and in another three patients, in whom the changed ratio was above the normal range. This overshoot (ie, fast strong increase in values to above normal) of the Cho/Cr ratio persisted for more than 6 months in three patients and for 1 year in one patient. Early clinical improvement with remaining signs of HE or subclinical HE was observed in three of the eight patients; all three of these patients fulfilled the Ross et al criteria for HE or subclinical HE based on the mI/Cr ratio but not those based on the Cho/Cr ratio (Fig 4). At MR imaging, we observed a slowly beginning decrease in BGH in seven of the eight patients.



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  		Figure 6a. (a-c) Representative transverse T1-weighted MR images (580/12), with the chosen volume of interest for spectroscopy outlined (box), and (d-f) corresponding MR spectroscopic results in one patient with overt HE 3 weeks (a and d), 3 months (b and e), and 1 year (c and f) after liver transplantation. Note that the spectroscopic renormalization—that is, decreased Glx/phosphocreatine (PCr) ratio and increased mI/phosphocreatine and Cho/phosphocreatine ratios—is almost complete 3 months after liver transplantation, with no further changes after liver transplantation. In contrast, BGH is diminished but still apparent after 3 months and is only completely resolved 1 year after liver transplantation. NAA = N-acetylaspartate.

 


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  		Figure 6b. (a-c) Representative transverse T1-weighted MR images (580/12), with the chosen volume of interest for spectroscopy outlined (box), and (d-f) corresponding MR spectroscopic results in one patient with overt HE 3 weeks (a and d), 3 months (b and e), and 1 year (c and f) after liver transplantation. Note that the spectroscopic renormalization—that is, decreased Glx/phosphocreatine (PCr) ratio and increased mI/phosphocreatine and Cho/phosphocreatine ratios—is almost complete 3 months after liver transplantation, with no further changes after liver transplantation. In contrast, BGH is diminished but still apparent after 3 months and is only completely resolved 1 year after liver transplantation. NAA = N-acetylaspartate.

 


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  		Figure 6c. (a-c) Representative transverse T1-weighted MR images (580/12), with the chosen volume of interest for spectroscopy outlined (box), and (d-f) corresponding MR spectroscopic results in one patient with overt HE 3 weeks (a and d), 3 months (b and e), and 1 year (c and f) after liver transplantation. Note that the spectroscopic renormalization—that is, decreased Glx/phosphocreatine (PCr) ratio and increased mI/phosphocreatine and Cho/phosphocreatine ratios—is almost complete 3 months after liver transplantation, with no further changes after liver transplantation. In contrast, BGH is diminished but still apparent after 3 months and is only completely resolved 1 year after liver transplantation. NAA = N-acetylaspartate.

 


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  		Figure 6d. (a-c) Representative transverse T1-weighted MR images (580/12), with the chosen volume of interest for spectroscopy outlined (box), and (d-f) corresponding MR spectroscopic results in one patient with overt HE 3 weeks (a and d), 3 months (b and e), and 1 year (c and f) after liver transplantation. Note that the spectroscopic renormalization—that is, decreased Glx/phosphocreatine (PCr) ratio and increased mI/phosphocreatine and Cho/phosphocreatine ratios—is almost complete 3 months after liver transplantation, with no further changes after liver transplantation. In contrast, BGH is diminished but still apparent after 3 months and is only completely resolved 1 year after liver transplantation. NAA = N-acetylaspartate.

 


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  		Figure 6e. (a-c) Representative transverse T1-weighted MR images (580/12), with the chosen volume of interest for spectroscopy outlined (box), and (d-f) corresponding MR spectroscopic results in one patient with overt HE 3 weeks (a and d), 3 months (b and e), and 1 year (c and f) after liver transplantation. Note that the spectroscopic renormalization—that is, decreased Glx/phosphocreatine (PCr) ratio and increased mI/phosphocreatine and Cho/phosphocreatine ratios—is almost complete 3 months after liver transplantation, with no further changes after liver transplantation. In contrast, BGH is diminished but still apparent after 3 months and is only completely resolved 1 year after liver transplantation. NAA = N-acetylaspartate.

 


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  		Figure 6f. (a-c) Representative transverse T1-weighted MR images (580/12), with the chosen volume of interest for spectroscopy outlined (box), and (d-f) corresponding MR spectroscopic results in one patient with overt HE 3 weeks (a and d), 3 months (b and e), and 1 year (c and f) after liver transplantation. Note that the spectroscopic renormalization—that is, decreased Glx/phosphocreatine (PCr) ratio and increased mI/phosphocreatine and Cho/phosphocreatine ratios—is almost complete 3 months after liver transplantation, with no further changes after liver transplantation. In contrast, BGH is diminished but still apparent after 3 months and is only completely resolved 1 year after liver transplantation. NAA = N-acetylaspartate.

 
During the 3–7 months after liver transplantation, the mI/Cr ratio in five of the eight patients and the Glx/Cr ratio in all eight patients returned to the normal value. No residual Cho/Cr ratio values below the normal range were found, whereas three of eight patients showed a persistent Cho/Cr ratio overshoot. In contrast, MR imaging still depicted BGH in seven of the eight patients. Clinically and psychometrically, however, these eight patients had a complete recovery without any residual signs of HE or subclinical HE. None of the Ross et al criteria was fulfilled in any patient (Fig 4).

Ten to 12 months after liver transplantation (Figs 4–6), complete normalization of the spectroscopic and imaging parameters was observed in seven of the eight patients (Figs 4, 5). One patient, who had biopsy-confirmed chronic rejection, still showed slightly elevated Glx/Cr ratio values within the overlap of normal and pathologic values (Fig 4a) and persisting BGH (Fig 5), but without clinical or psychometric signs of HE or subclinical HE.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
REFERENCES
 
It has been shown repeatedly that for HE and subclinical HE, a specific pattern of cerebral metabolic changes exists in the brain; and this pattern, even in its mildest form, can be noninvasively detected by using short echo-time MR spectroscopy (8,13–15). To our knowledge, such simultaneous and substantial changes in cerebral mI/Cr and Cho/Cr ratios, with or without a Glx/Cr ratio change, have not yet been described in association with other encephalopathies (8,27–30). In agreement with our experience, this high sensitivity is underlined by reports of single patients who exhibited mild changes in MR spectroscopic findings before developing HE and in whom psychometric test results were still normal (8,11,14). In our opinion, the clinical value of MR spectroscopy is not restricted by the fact that, at present, it is not possible to discriminate between subclinical HE and low-grade HE with MR spectroscopy alone, because differentiating grade 0 from grade 1 HE, in contrast to identifying a patient with grade 0 disease, is of minor practical importance.

If liver disease, the condition underlying HE, is solely responsible for the cerebral metabolite changes described, then we can expect reversibility of metabolite levels after liver transplantation if no persistent brain damage has occurred. In good agreement with our results of complete renormalization of the spectroscopically detectable brain metabolite changes, there are early reports of mI and Cho level renormalization combined with renormalization of the Glx level in a total of six patients who underwent single MR spectroscopic examinations before and after liver transplantation (9,31) without longer follow-up. According to preliminary results of conventional drug therapy, however, although this treatment improves the symptoms of HE, it does not seem to restore the MR spectroscopic profile (9). To our knowledge, no results of time-dependent MR spectroscopic examinations performed after liver transplantation had been reported before now. Our study results demonstrate that the return of brain metabolite values to their normal ranges, as well as clinical recovery, occurs within the first 3–7 months after liver transplantation.

Furthermore, our results confirm the validity of the Ross et al criteria (8) for predicting HE or subclinical HE with MR spectroscopy to a large extent: In only three post–liver transplantation examinations performed in patients with remaining signs of HE or subclinical HE were the Cho/Cr ratios slightly too high to fulfill the Ross et al criterion for HE or subclinical HE, whereas the mI/Cr ratio criterion was fulfilled in every case of HE or subclinical HE. However, these findings are in good agreement with those of Ross et al (8), who found that the mI/Cr ratio criterion alone has a sensitivity of 80%–85% for the detection of HE or subclinical HE and therefore is the most important of the criteria. In particular, we did not encounter any control subject or patient examination that was negative for HE or subclinical HE in which a single one of the three Ross et al criteria was fulfilled.

Despite these encouraging MR spectroscopic results, the roles of Cho and mI in the brain, and especially in HE, are not completely understood. In chronic liver dysfunction, decreased urea cycle activity seems to be responsible for the elevated cerebral glutamine level owing to its increased synthesis in astrocytes (16,32). It has been shown that mI, apart from contributing to ion flux, may serve as an organic osmolite and has an important role in the volume regulation of astrocytes (16,33,34). This has been confirmed with in vivo examinations, in which decreased or increased cerebral mI was found in patients with hyponatremia or hypernatremia, respectively (16,35,36). In addition, the results of in vitro cell studies have demonstrated osmotic regulation of the expression of genes for encoding mI transporters in the plasma membrane. Glia cell swelling due to ammonia induces high intracellular glutamine concentrations, and compensatory cellular mI release has been suggested as a major cause of the development of HE (16).

These findings are partly based on the results of in vitro studies, in which astrocyte swelling was influenced by ammonia and confirmed by using in vivo studies in patients with valproate (37) or ornithine transcarbamylase deficiency–induced hyperammonemia, in whom decreased mI levels and clinical symptoms of HE were found (9). These findings are, in principle, confirmed by our results: In the patients with HE or subclinical HE, an elevated Glx/Cr ratio combined with a decreased mI/Cr ratio before liver transplantation and simultaneous recovery afterward were observed.

From the results of other studies it is known that about 70%–80% of patients with chronic liver disease show areas of BGH at T1-weighted imaging (19–21). The importance of this finding remains controversial. Although Brunberg et al (21) could not find a correlation between these signal intensity changes and either laboratory indexes of hepatic dysfunction or neurologic status, in a prospective study involving 30 patients with chronic liver disease, a strong correlation between BGH and plasma ammonia levels and an association with neurologic symptoms were found (19).

Strong indications that the BGH might be caused by deposition of paramagnetic manganese exist, because manganese shortens tissue T1 relaxation times and thus leads to elevated signal intensity at T1-weighted MR imaging. Manganese passes the blood brain barrier and is slowly excreted through the biliary system. Chronic liver disease may influence manganese homeostasis (38). In animal studies, elevated manganese concentrations in the basal ganglia and in the serum were found in monkeys in cases of intravenous administration of manganese chloride, whereas the serum levels remained normal during the oral administration of manganese chloride (39). Similar results have recently been described in children who received long-term parenteral nutrition. The elevated serum manganese levels were associated with cholestasis and neurologic disorders, and BGH was seen independently of liver disease on the images obtained in the patients with hypermanganesaemia (40). These findings indicate that manganese may be responsible for the BGH when normal (ie, enteral) regulation mechanisms for homeostasis (41) are bypassed by intravenous application or manganese excretion is reduced owing to liver dysfunction (20,38,40).

If the deposition of manganese is the reason for the BGH, then one could expect partial or complete reversibility after reduction of the manganese level or improvement of liver function, as long as there is no persisting cerebral cell damage. There are several reports of partial but not complete remission of BGH 1 year after the termination of parenteral nutrition (42), 3 months after the completion of intensive conservative treatment for HE (43), and 9 months after the embolization of portal systemic shunts.

Furthermore, there are several reports of the disappearance of BGH after liver transplantation. Devenyi et al (22) reported on an 8-year-old girl with end-stage liver disease, elevated manganese serum levels, and dystonia who had a complete remission 2 months after liver transplantation, with improvement of neurologic functions, renormalization of manganese serum levels, and complete resolution of the BGH. Pujol et al (23) described 21 patients with advanced liver disease who underwent MR imaging before and 10–20 months after liver transplantation and exhibited a complete resolution of the BGH in all cases. Although to our knowledge, no reports of sequential follow-up examinations after liver transplantation exist, the findings in the latter report are consistent with our results—that is, complete normalization of BGH on T1-weighted images occurs within 1 year after liver transplantation in all patients except those with chronic rejection. The time-course of BGH renormalization, however, seems to be delayed with respect to spectroscopically detectable metabolite changes. The latter, as well as the neuropsychologic signs of HE or subclinical HE, are almost completely reversed 3–7 months after liver transplantation, whereas the BGH is diminished but still clearly detectable during this interval (Figs 5, 6). Thus, the restitution of normal signal intensity in the basal ganglia on T1-weighted MR images seems to be a slower and more continuous process, but again, the complete reversibility of BGH indicates that persisting cell damage is less probable.


   FOOTNOTES
 
Abbreviations: BGH = basal ganglia high signal intensity, Cho = choline, Cr = creatine, Glx = glutamine and glutamate, HE = hepatic encephalopathy, mI = myo-inositol

Author contributions: Guarantors of integrity of entire study, T.N., W.G.; study concepts and design, T.N., W.G.; definition of intellectual content, T.N., R.V.; literature research, J.M., S.K.; clinical studies, T.N., U.S., D.S., I.M.; experimental studies, T.N., U.S., U.K., I.M.; data acquisition, T.N., U.S., D.S.; data analysis, U.S., J.M.; statistical analysis, U.S., T.N., U.K.; manuscript preparation, T.N., D.S.; manuscript editing, T.N., W.G., U.K.; manuscript review, all authors.


   REFERENCES
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 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 

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