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Viability assessment of magnetic resonance spectroscopy for the detection of minimal hepatic encephalopathy severity
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Viability assessment of magnetic resonance spectroscopy for the detection of minimal hepatic encephalopathy severity Ling-ping Meng a,1 , Yuan-chang Chen b,1 , Yue-hua Li b,∗ , Jin-shui Zhu c , Jian-lin Ye d a
Department of Radiology, Jinshan Branch of Shanghai No. 6 People’s Hospital, No.147 Jian Kang Road, Shanghai, China Institute of Diagnostic and Interventional Radiology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yi Shan Road, Shanghai, China c Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yi Shan Road, Shanghai, China d Department of Psychiatry, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yi Shan Road, Shanghai, China b
a r t i c l e
i n f o
Article history: Received 26 February 2015 Received in revised form 7 June 2015 Accepted 25 June 2015 Keywords: Minimal hepatic encephalopathy Hepatic cirrhosis Magnetic resonance spectroscopy Anterior cingulate cortex Basal ganglia
a b s t r a c t Objective: To evaluate regional cerebral metabolic changes in minimal hepatic encephalopathy (MHE) patients using magnetic resonance spectroscopy (MRS) in 3T scanner. Materials and methods: This study comprised 30 cirrhotic patients with MHE, 29 cirrhotic patients without MHE and 30 healthy volunteers. Single-voxel proton MRS data in the anterior cingulate cortex (ACC) and basal ganglia were acquired using a 3-T scanner. The concentrations of N-acetylaspartate (NAA), mI (myo-inositol), glutamate (Glu), glutamine (Gln) and creatine (Cr) were obtained by LC-model software. Statistical analysis was performed to evaluate the differences between the three groups. Results: There was a significant increase in Glu for the cirrhotic patients, particularly the MHE patients. There was an elevation of Gln in the cirrhotic patients, but not in all cirrhotic patients or controls. There was a significant decrease in mI for the cirrhotic patients, but no significant difference between the two cirrhosis groups. There was no significant difference in NAA between the three groups. Conclusions: MRS using a 3-T MR scanner could detect cerebral metabolic changes in cirrhotic patients with MHE. Glu levels were elevated in cirrhotic patients with MHE; Glu levels could be used as a sensitive indicator to evaluate the severity of MHE in patients with cirrhosis. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Minimal hepatic encephalopathy (MHE) is characterized by the presence of cognitive impairment on psychometric testing and/or the slowing of electroencephalographic (EEG) mean cycle frequency in the absence of any clinically overt signs. This condition is frequently seen in patients with cirrhosis [1]. Hepatic encephalopathy (HE) syndrome is essentially a neuropsychiatric condition and is therefore traditionally diagnosed by neuropsychological tests, which are not specific and do not reveal the underlying pathology [2]. Early diagnosis of MHE might be crucial considering the fact that after a follow-up period of three years, around 50% of cirrhotic patients with MHE present with clinically overt HE, compared with only 8% of patients without MHE [3]. This underscores the prognos-
∗ Corresponding author. Fax: +86 021 64844183. E-mail address: li yue [email protected] (Y.-h. Li). 1 These authors contributed equally to this work.
tic significance of MHE, and is likely to impact on the quality of life of these patients [1]. The pathophysiology, natural history, and prognosis of cirrhosisassociated neuropsychiatric deficits are not fully understood, and the data on this issue are controversial [4]. Recent studies have shown that these deficits are associated with changes in metabolic brain patterns, which may be reversed by a reduction in blood ammonia level [3]. However, long-term persistence of these symptoms following liver transplantation has been reported, and it is suggested that this disorder is neurodegenerative in nature [3]. Adequate clinical neuropsychiatric evaluation of these patients remains difficult because neuropsychiatric symptoms associated with low grade encephalopathy are multiform and sometimes subtle. This problem is further exacerbated in the case of MHE, for which patients only demonstrate deficits on neuropsychological tests [5]. Furthermore, these tests can be subject to confounding factors such as age, superimposed mood disorders, and level of education [6]. Therefore, there has been increasing interest in the use of noninvasive imaging techniques, such as magnetic resonance spectroscopy (MRS), to assist in the evaluation of MHE [7].
http://dx.doi.org/10.1016/j.ejrad.2015.06.027 0720-048X/© 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: L.-p. Meng, et al., Viability assessment of magnetic resonance spectroscopy for the detection of minimal hepatic encephalopathy severity, Eur J Radiol (2015), http://dx.doi.org/10.1016/j.ejrad.2015.06.027
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H1 -MRS has been used extensively to evaluate brain changes in cirrhosis patients [6,8]. In patients with HE, it has been observed that myo-inositol (mI) was reduced with increasing concentrations of glutamate/glutamine (Glx) [9]. Glutamate (Glu) is an excitatory neurotransmitter, which is considered to play a role in the pathophysiology of HE [10]. Previous studies have reported changes in Glx, rather than individual changes in Glu and glutamine (Gln) [8]. Since the blood–brain barrier (BBB) is permeable to Gln, which is not a neurotransmitter, there is uncertainty regarding the results of the studies that focused on Glx. In this study, we conducted MRS using a high-magnetic field MR (3T) to separate Glu from Gln, and analyzed the data to determine the correlation between NAA, Cr, mI, Gln, and Glu levels and the pathophysiology of HE. 2. Material and methods 2.1. Subjects The subjects were divided into three groups. Group I: 33 patients diagnosed with liver cirrhosis with MHE; group II: 30 patients diagnosed with liver cirrhosis without HE; and group III: 30 healthy controls. The patients were clinically evaluated during their initial assessment. The cognitive evaluation included a psychiatric history and the mini-mental status examination (MMSE). Patients scoring less than 24 on the MMSE were classified as cognitively impaired and were excluded from the study [3]. Liver cirrhosis was diagnosed using general evaluation methods, such as imaging techniques (e.g., abdominal ultrasonography, computed tomography), histological examination and blood biochemical data. The exclusion criteria included: claustrophobia during MR examination; age of less than 18 or more than 75 years; active alcoholism during the 3 months before the study; HE grades of II–IV; a Child–Pugh score (which assesses the severity of liver disease) of C; additional neurological or psychiatric disease; treatment with psychotropic drugs or other drugs known to alter neuropsychological function; gastrointestinal bleeding or infection within 1 week before the study; and previous treatment with shunt procedures. Control subjects were recruited through advertisements. None of the controls had any history of neurological or psychiatric illness, metabolic disorders, alcohol or drug abuse, head injury or liver disease. All patients underwent a detailed clinical assessment, including a neurological examination. Written informed consent was obtained from each participant included in this study and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. This study was approved by the Ethics Committee of the local Institutional Review Board. 2.2. Clinical neuropsychological tests A number connection test type A (NCT-A) and a digit symbol test (DST) were performed, as recommended by the international HE working party at the 11th World Congress of Gastroenterology, Vienna, 1998 [1]. Results were considered abnormal when the test score was 2 standard deviations above or below the age- and education-matched controls [11]. Patients with abnormal NCT-A and/or DST results, but without overt clinical HE, were classified as having MHE [1]. 2.3. Laboratory examination Blood biochemistry tests, including prothrombin time, protein metabolism tests (e.g., total protein, globulin, albumin, the ratio of albumin and globulin), bilirubin metabolism tests (e.g.,
Fig. 1. Metabolite changes in the ACC for the cirrhotic patients with MHE (49-yearold, male). It was revealed that Glu was present at 2.35 ppm, Gln at 2.45 ppm, mI at 3.55 ppm, Cr at 3.02 ppm, and NAA at 2.01 ppm. ACC, anterior cingulate cortex; MHE, minimal hepatic encephalopathy; Glu, glutamate; Gln, glutamine; mI, myo-inositol; Cr, creatine; NAA, N-acetylaspartate.
total bilirubin, direct bilirubin, indirect bilirubin), glutamic pyruvic transaminase and glutamic oxaloacetic transaminase, were performed within one week prior to MR scanning for all patients. The above-mentioned tests were used to calculate the Child–Pugh score to assess the severity of liver disease [11]. Venous blood ammonia tests were also conducted. 2.4. MR examination In vivo single-voxel MRS was performed using a Philips 3-T MRI system (Intera Achieva 3.0T/Quasar, Philips Medical System, The Netherlands) equipped with an 8-channel phase coil. Anatomical T1-weighted MR images were obtained using the following parameters: repetition time (TR) = 550 ms; echo time (TE) = 10 ms; flip angle = 60◦ ; field of view (FOV) = 21 cm; slice thickness = 3 mm; slice spacing = 0.1 mm. H1 -MRS was performed for quantification analysis of metabolite concentrations in the brain. Initially, 2D-T1W imaging data in the coronal and sagittal regions were obtained for image-guided localization of the voxels of interest for spectroscopic data acquisition. The MRS evaluation was conducted in the ACC and the basal ganglia (Fig. 1). Single-voxel MRS was performed using a stimulated-echo acquisition mode (STEAM) sequence with the following parameters: TR = 2000 ms; TE = 72 ms; mixing time (TM) = 6 ms; voxel = 20 × 20 × 20 mm3 ; total number of points = 2048; averages = 256. Eight-step phase cycling was used to suppress unwanted signals or artifacts. The total scan time was 25 min. It was revealed that Glu was present at 2.35 ppm, Gln at 2.45 ppm, mI at 3.55 ppm, Cr at 3.02 ppm, and NAA at 2.01 ppm [12]. All these MRS metabolites were quantified by fitting experimental data in the frequency domain using the LC model algorithm. 2.5. Statistical analysis Statistical analysis was performed using SPSS v.11.5 software (SPSS Inc., Chicago, IL, USA). Quantitative variables were expressed as means (standard deviations), and categorical variables as frequencies or percentages. Differences between patients and healthy controls were tested using the two-tailed t-test. Differences within each group were tested with the paired t-test. The independent sample Student’s t-test was used to compare metabolite concentration in the ACC and basal ganglia between the healthy controls
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Table 1 The clinical and laboratory parameters for the three diagnostic groups. Index
Group I
Group II
Group III
P value
(n = 30)
(n = 29)
(n = 30)
p1
p2
p3
Male/female Age
20/13 48.1 ± 8.2
16/14 45.1 ± 9.5
15/15 44.2 ± 10.5
0.6164 0.1836
0.4530 0.1029
1.000 0.7290
Etiology of liver disease Post-hepatitis Alcoholic Other Albumin(g/L) Prothrombin time(s) International normalized ratio Bilirubin (mol/L) Venous ammonia (mol/L) Child–Pugh score Number connection test A(s) Digit symbol test
15 7 8 37.62 ± 4.80 17.65 ± 3.90 1.65 ± 0.38 43.25 ± 14.60 86.98 ± 25.71 6.5 ± 2.2 65.28 ± 24.69 29.32 ± 12.42
17 8 5 35.58 ± 3.53 16.10 ± 1.84 1.72 ± 0.17 47.40 ± 20.42 75.27 ± 21.55 5.6 ± 3.2 50.15 ± 25.22 48.65 ± 12.11
– – – – – – – – – 39.21 ± 14.52 55.37 ± 13.68
0.3097 0.7686 0.5423 0.0614 0.0517 0.3573 0.3538 0.0559 0.1948 0.0192 <0.0001
– – – – – – – –
– – – – – – – –
<0.0001 <0.0001
0.0440 0.0486
p 1: P value between group I and group II; p 2: P value between group I and group III; p 3: P value between group II and group III.
Table 2 The concentrations of the metabolites (mean ± SD) detected from the 2D MRS peak volumes.
BG (mM)
ACC (mM)
NAA Glu Glna mI Cr NAA Glu Glna mI Cr
Group I
Group II
Group III
P value
(n = 30)
(n = 29)
(n = 30)
p1
p2
p3
8.682 ± 1.218 17.578 ± 3.223 3.875 ± 1.641 3.923 ± 1.595 6.219 ± 1.176 9.327 ± 1.116 17.116 ± 1.715 3.052 ± 1.240 3.821 ± 1.105 6.023 ± 1.295
8.873 ± 1.361 13.489 ± 2.956 3.348 ± 1.516 3.593 ± 1.306 6.447 ± 1.232 9.632 ± 1.682 12.159 ± 1.851 3.412 ± 1.547 3.515 ± 1.207 6.293 ± 1.306
9.242 ± 1.765 8.893 ± 1.272 1.591 ± 1.277 5.827 ± 1.004 6.752 ± 1.163 8.943 ± 1.362 8.451 ± 1.246 1.633 ± 0.748 5.848 ± 1.176 6.477 ± 1.062
0.5719 <0.0001 0.4694 0.3891 0.4700 0.4137 <0.0001 0.5702 0.3138 0.4286
0.1580 <0.0001 0.0153 <0.0001 0.0828 0.2371 <0.0001 0.0343 <0.0001 0.1430
0.3734 <0.0001 0.0400 <0.0001 0.3322 0.0887 <0.0001 0.0342 <0.0001 0.5544
p 1: P value between Group I and Group II; p 2: P value between Group I and Group III; p 3: P value between Group II and Group III. a Gln was detected in 11 patients in group I, 9 patients in group II, and 5 healthy subjects in group III. Cr = creatine; NAA = N-acetyl aspartate; Glu = glutamate; Gln = glutamine; mI = myo-inositol; ACC = anterior cingulate cortex; BG = basal ganglia.
and cirrhotic patients. P-values less than 0.05 were considered statistically significant. 3. Results Four patients (three in group I and one in group II) did not complete the MR examination because of a long scan time. The remaining patients were divided into the following groups: group I (cirrhosis patients with MHE), 30 patients (14 females and 16 males); group II (cirrhosis patients without MHE), 29 patients (14 females and 15 males); and group III (healthy controls), 30 patients (17 females and 13 males). The clinical and laboratory parameters for the three groups are shown in Table 1. The MRS characteristics in the left ACC and left basal ganglia are presented in Table 2. The metabolic changes in the left ACC are described as follows (Fig. 2). There was a significant increase of Glu in the cirrhotic patients (P < 0.001, P < 0.001). A statistical difference was revealed for Glu between patients with and without MHE (P < 0.001). Gln significantly increased in the cirrhotic patients (P = 0.0409, P = 0.0336), but it could not be detected in all cirrhotic patients or the healthy controls. There was a significant decrease in mI for the cirrhotic patients (P = 0.0132, P = 0.0059), but there was no significant difference between the patients with and without MHE (P = 0.7028). There was no significant difference in NAA between the three groups. Our findings indicated elevated Glu in the MHE patients, and decreased mI/Cr in the cirrhotic patients in the left ACC. The findings in the basal ganglia region were similar to the ACC region and the findings for right ROI were similar to the left side.
Fig. 2. Metabolite changes in the ACC for the cirrhotic patients with MHE (group I), the cirrhotic patients without MHE (group II) and the healthy volunteers (group III). *P value < 0.05. Glu significantly increased in the cirrhotic patients, and the difference in Glu was statistically significant in patients with and without MHE. Gln significantly increased in the cirrhotic patients, but it could not be detected in all cirrhotic patients or healthy controls. mI significantly decreased in the cirrhotic patients; however, there was no significant difference between the patients with and without MHE. ACC, anterior cingulate cortex; MHE, minimal hepatic encephalopathy; Glu, glutamate; Gln, glutamine; mI, myo-inositol.
4. Discussion Previous relevant studies have mainly concentrated on the metabolic changes of the brain in cirrhotic patients with clinical HE [8]. The main purpose of this study was to quantitatively study
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the brain changes in cirrhotic patients with MHE and cirrhotic without MHE, compared to healthy controls. Furthermore, we used the absolute quantification of the metabolite concentrations (Glu, Gln, mI, NAA and Cr) instead of the metabolic ratios. With the increasing availability of the 3-T MR scanner, the reliability of separating the Glx signals in the brain has improved [12]. In our study, we conducted MRS using a 3-T MR scanner, and found that we were not able to detect Gln in all patients or control subjects; however, an increase in Glu could be detected in all patients with cirrhosis. There was an increase of Glu in patients with cirrhosis, and a significant difference in Glu between patients with and without MHE, which indicated that the increased Glx signal intensity in the brain observed in cases of liver cirrhosis is mainly attributable to an increase in Glu. International society for hepatic encephalopathy and nitrogen metabolism (ISHEN) has suggested to classify HE according to worsening of cognitive function from unimpaired (without any clinical, neurophysiological or neuropsychometric changes) to covert (minimal HE and Grade I according West-Haven) and overt (Grade II according West-Haven) [13]. The patients with MHE are anxious, agitated, have even convulsions and difficulties sleeping, because that Glu is an excitatory neurotransmitter. In the early stage of the disease, in case of hyperammonemia brain participates in conversion of ammonia. High amount of Glu in astrocytes Gln synthetase (GS) transforms into Gln that causes the osmotic disbalance in the cell. Gln is transported to neurons where it is deaminated into Glu by glutaminase. Glu stimulates postsynaptic receptors of neurons [14]. Thus, the difference in Glu levels for patients at the MHE stage can provide an objective measure in the clinical setting. The patients with covert HE are more commonly slower, sleepy, etc. Because of chronic hyperammonemia the mechanisms to keep homeostasis turn on. The amount of Glu receptors in postsynaptic membrane decreases, carriers of Glu are inhibited and less of Glu returns back into astrocytes. High amount of Glu accumulates in the postsynaptic space and suppression of Glu receptors occurs [14]. Moreover, a net increase in inhibitory neurotransmission, due to an imbalance between the functional status of inhibitory (e.g., GABA) and excitatory (e.g., glutamate) neurotransmitter systems [15]. So the level of Glu could not reflect the severity of HE. In this study, we found that Gln concentration increased in the cirrhotic patients, but there was no significant difference between patients with and without MHE. The level of Gln increases in the early stages of MHE; however, the compensatory function of astrocytes can transfer Gln out of the brain [14]. As the disease progresses, Gln quickly increases. Others have reported that Gln increased significantly in the advanced stages of HE [12]. We also found that mI decreased in the cirrhotic patients, but there was no significant difference between the cirrhotic patients with and without MHE. Myo-inositol is an organic osmolyte presumed to act as an astrocyte compensatory tool to buffer an ammonia-induced increase in Gln within astrocytes [16]. However, it takes time to achieve astrocyte volume homeostasis [17]. Minimal hepatic encephalopathy might occur too slightly or too rapidly to allow this compensatory shift. This may explain why there were no significant differences in mI for patients with and without MHE, which indicates that mI might not correlate with the severity of HE. In this study, we used the absolute quantification of the metabolite concentrations instead of the metabolic ratios, which would not be affected by the variability of the internal reference. To express as metabolic ratios, the method for a quantitative analysis requires the use of some references. In brain spectroscopy the total Cr signal has been serving fairly well as an internal reference [18]. However, the concentration of Cr would change in many diseases, such as HE [19]. The results showed that the concentration of Cr was higher in the healthy control group than in the two cirrhosis groups, although these differences did not have the statistical significance. The brain
metabolism changes maybe occurred in the cirrhotic patients and the concentrations of Cr might also change in these patients, thus there would be some bias caused by using the ratios to Cr. Cerebral ammonia metabolism is considered to play a key role in the pathophysiology of HE in patients with acute and chronic liver failure [4,20]. But the “ammonia intoxication hypothesis” cannot fully explain why only some cirrhotic patients went on to develop HE, even though all patients had the same severity of cirrhosis [17]. The ammonia levels correlate poorly with severity of HE [14,21]. In our study, patients with cirrhosis had abnormal venous blood ammonia; while, there were no significant differences in blood ammonia between the cirrhotic patients with and without MHE. Child–Pugh class C cirrhotic patients are likely to develop severe HE [11], so we excluded these patients and only chose the patients with Child-Pugh class A and B. Adequate clinical neuropsychiatric evaluation of these patients remains difficult because neuropsychiatric symptoms associated with low grade encephalopathy are multiform and sometimes subtle. This problem is further exacerbated in the case of MHE, for which patients only demonstrate deficits on neuropsychological tests [5]. Furthermore, these tests can be subject to confounding factors such as age, superimposed mood disorders, and level of education [6]. Therefore, there has been increasing interest in the use of noninvasive imaging techniques, such as magnetic resonance spectroscopy (MRS), to assist in the evaluation of MHE [7]. It has been shown that MHE patients show psychomotor slowing and executive dysfunction, whereas other cognitive abilities are relatively preserved, reflecting a disorder that mainly affects the prefrontal cortex and its connections with the basal ganglia [5,22]. The ACC plays an important role in cognitive functions, such as conflict monitoring, reward anticipation, decision-making, empathy and emotion [11]. In addition, the ACC plays an important role in maintaining the resting state of the brain’s functional network [11]. Thus, the basal ganglia and ACC seem to be appropriate locations to observe functional and metabolite changes in patients with cirrhosis. We acknowledge the following study limitations that may limit the generalization of our results. The comparison of the extent of spectral changes in the ACC and basal ganglia versus other brain regions in cirrhotic patients was not possible in this study because of the scanning time. Other studies comparing spectral changes in the occipital, frontal and parietal lobes have showed heterogeneous results [3,23]. Whether more significant spectral changes are seen in the ACC and basal ganglia compared to other brain regions in cirrhotic patients deserves further investigation. In summary, we found that MRS using a 3-T MR scanner could be used to detect cerebral metabolic changes in cirrhotic patients with MHE. The typical MRS brain characteristic in these patients was elevated Glu, which could be used as a sensitive indicator to evaluate the MHE severity in patients with cirrhosis.
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European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Viability assessment of magnetic resonance spectroscopy for the detection of minimal hepatic encephalopathy severity Ling-ping Meng a,1 , Yuan-chang Chen b,1 , Yue-hua Li b,∗ , Jin-shui Zhu c , Jian-lin Ye d a
Department of Radiology, Jinshan Branch of Shanghai No. 6 People’s Hospital, No.147 Jian Kang Road, Shanghai, China Institute of Diagnostic and Interventional Radiology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yi Shan Road, Shanghai, China c Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yi Shan Road, Shanghai, China d Department of Psychiatry, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yi Shan Road, Shanghai, China b
a r t i c l e
i n f o
Article history: Received 26 February 2015 Received in revised form 7 June 2015 Accepted 25 June 2015 Keywords: Minimal hepatic encephalopathy Hepatic cirrhosis Magnetic resonance spectroscopy Anterior cingulate cortex Basal ganglia
a b s t r a c t Objective: To evaluate regional cerebral metabolic changes in minimal hepatic encephalopathy (MHE) patients using magnetic resonance spectroscopy (MRS) in 3T scanner. Materials and methods: This study comprised 30 cirrhotic patients with MHE, 29 cirrhotic patients without MHE and 30 healthy volunteers. Single-voxel proton MRS data in the anterior cingulate cortex (ACC) and basal ganglia were acquired using a 3-T scanner. The concentrations of N-acetylaspartate (NAA), mI (myo-inositol), glutamate (Glu), glutamine (Gln) and creatine (Cr) were obtained by LC-model software. Statistical analysis was performed to evaluate the differences between the three groups. Results: There was a significant increase in Glu for the cirrhotic patients, particularly the MHE patients. There was an elevation of Gln in the cirrhotic patients, but not in all cirrhotic patients or controls. There was a significant decrease in mI for the cirrhotic patients, but no significant difference between the two cirrhosis groups. There was no significant difference in NAA between the three groups. Conclusions: MRS using a 3-T MR scanner could detect cerebral metabolic changes in cirrhotic patients with MHE. Glu levels were elevated in cirrhotic patients with MHE; Glu levels could be used as a sensitive indicator to evaluate the severity of MHE in patients with cirrhosis. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Minimal hepatic encephalopathy (MHE) is characterized by the presence of cognitive impairment on psychometric testing and/or the slowing of electroencephalographic (EEG) mean cycle frequency in the absence of any clinically overt signs. This condition is frequently seen in patients with cirrhosis [1]. Hepatic encephalopathy (HE) syndrome is essentially a neuropsychiatric condition and is therefore traditionally diagnosed by neuropsychological tests, which are not specific and do not reveal the underlying pathology [2]. Early diagnosis of MHE might be crucial considering the fact that after a follow-up period of three years, around 50% of cirrhotic patients with MHE present with clinically overt HE, compared with only 8% of patients without MHE [3]. This underscores the prognos-
∗ Corresponding author. Fax: +86 021 64844183. E-mail address: li yue [email protected] (Y.-h. Li). 1 These authors contributed equally to this work.
tic significance of MHE, and is likely to impact on the quality of life of these patients [1]. The pathophysiology, natural history, and prognosis of cirrhosisassociated neuropsychiatric deficits are not fully understood, and the data on this issue are controversial [4]. Recent studies have shown that these deficits are associated with changes in metabolic brain patterns, which may be reversed by a reduction in blood ammonia level [3]. However, long-term persistence of these symptoms following liver transplantation has been reported, and it is suggested that this disorder is neurodegenerative in nature [3]. Adequate clinical neuropsychiatric evaluation of these patients remains difficult because neuropsychiatric symptoms associated with low grade encephalopathy are multiform and sometimes subtle. This problem is further exacerbated in the case of MHE, for which patients only demonstrate deficits on neuropsychological tests [5]. Furthermore, these tests can be subject to confounding factors such as age, superimposed mood disorders, and level of education [6]. Therefore, there has been increasing interest in the use of noninvasive imaging techniques, such as magnetic resonance spectroscopy (MRS), to assist in the evaluation of MHE [7].
http://dx.doi.org/10.1016/j.ejrad.2015.06.027 0720-048X/© 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: L.-p. Meng, et al., Viability assessment of magnetic resonance spectroscopy for the detection of minimal hepatic encephalopathy severity, Eur J Radiol (2015), http://dx.doi.org/10.1016/j.ejrad.2015.06.027
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H1 -MRS has been used extensively to evaluate brain changes in cirrhosis patients [6,8]. In patients with HE, it has been observed that myo-inositol (mI) was reduced with increasing concentrations of glutamate/glutamine (Glx) [9]. Glutamate (Glu) is an excitatory neurotransmitter, which is considered to play a role in the pathophysiology of HE [10]. Previous studies have reported changes in Glx, rather than individual changes in Glu and glutamine (Gln) [8]. Since the blood–brain barrier (BBB) is permeable to Gln, which is not a neurotransmitter, there is uncertainty regarding the results of the studies that focused on Glx. In this study, we conducted MRS using a high-magnetic field MR (3T) to separate Glu from Gln, and analyzed the data to determine the correlation between NAA, Cr, mI, Gln, and Glu levels and the pathophysiology of HE. 2. Material and methods 2.1. Subjects The subjects were divided into three groups. Group I: 33 patients diagnosed with liver cirrhosis with MHE; group II: 30 patients diagnosed with liver cirrhosis without HE; and group III: 30 healthy controls. The patients were clinically evaluated during their initial assessment. The cognitive evaluation included a psychiatric history and the mini-mental status examination (MMSE). Patients scoring less than 24 on the MMSE were classified as cognitively impaired and were excluded from the study [3]. Liver cirrhosis was diagnosed using general evaluation methods, such as imaging techniques (e.g., abdominal ultrasonography, computed tomography), histological examination and blood biochemical data. The exclusion criteria included: claustrophobia during MR examination; age of less than 18 or more than 75 years; active alcoholism during the 3 months before the study; HE grades of II–IV; a Child–Pugh score (which assesses the severity of liver disease) of C; additional neurological or psychiatric disease; treatment with psychotropic drugs or other drugs known to alter neuropsychological function; gastrointestinal bleeding or infection within 1 week before the study; and previous treatment with shunt procedures. Control subjects were recruited through advertisements. None of the controls had any history of neurological or psychiatric illness, metabolic disorders, alcohol or drug abuse, head injury or liver disease. All patients underwent a detailed clinical assessment, including a neurological examination. Written informed consent was obtained from each participant included in this study and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. This study was approved by the Ethics Committee of the local Institutional Review Board. 2.2. Clinical neuropsychological tests A number connection test type A (NCT-A) and a digit symbol test (DST) were performed, as recommended by the international HE working party at the 11th World Congress of Gastroenterology, Vienna, 1998 [1]. Results were considered abnormal when the test score was 2 standard deviations above or below the age- and education-matched controls [11]. Patients with abnormal NCT-A and/or DST results, but without overt clinical HE, were classified as having MHE [1]. 2.3. Laboratory examination Blood biochemistry tests, including prothrombin time, protein metabolism tests (e.g., total protein, globulin, albumin, the ratio of albumin and globulin), bilirubin metabolism tests (e.g.,
Fig. 1. Metabolite changes in the ACC for the cirrhotic patients with MHE (49-yearold, male). It was revealed that Glu was present at 2.35 ppm, Gln at 2.45 ppm, mI at 3.55 ppm, Cr at 3.02 ppm, and NAA at 2.01 ppm. ACC, anterior cingulate cortex; MHE, minimal hepatic encephalopathy; Glu, glutamate; Gln, glutamine; mI, myo-inositol; Cr, creatine; NAA, N-acetylaspartate.
total bilirubin, direct bilirubin, indirect bilirubin), glutamic pyruvic transaminase and glutamic oxaloacetic transaminase, were performed within one week prior to MR scanning for all patients. The above-mentioned tests were used to calculate the Child–Pugh score to assess the severity of liver disease [11]. Venous blood ammonia tests were also conducted. 2.4. MR examination In vivo single-voxel MRS was performed using a Philips 3-T MRI system (Intera Achieva 3.0T/Quasar, Philips Medical System, The Netherlands) equipped with an 8-channel phase coil. Anatomical T1-weighted MR images were obtained using the following parameters: repetition time (TR) = 550 ms; echo time (TE) = 10 ms; flip angle = 60◦ ; field of view (FOV) = 21 cm; slice thickness = 3 mm; slice spacing = 0.1 mm. H1 -MRS was performed for quantification analysis of metabolite concentrations in the brain. Initially, 2D-T1W imaging data in the coronal and sagittal regions were obtained for image-guided localization of the voxels of interest for spectroscopic data acquisition. The MRS evaluation was conducted in the ACC and the basal ganglia (Fig. 1). Single-voxel MRS was performed using a stimulated-echo acquisition mode (STEAM) sequence with the following parameters: TR = 2000 ms; TE = 72 ms; mixing time (TM) = 6 ms; voxel = 20 × 20 × 20 mm3 ; total number of points = 2048; averages = 256. Eight-step phase cycling was used to suppress unwanted signals or artifacts. The total scan time was 25 min. It was revealed that Glu was present at 2.35 ppm, Gln at 2.45 ppm, mI at 3.55 ppm, Cr at 3.02 ppm, and NAA at 2.01 ppm [12]. All these MRS metabolites were quantified by fitting experimental data in the frequency domain using the LC model algorithm. 2.5. Statistical analysis Statistical analysis was performed using SPSS v.11.5 software (SPSS Inc., Chicago, IL, USA). Quantitative variables were expressed as means (standard deviations), and categorical variables as frequencies or percentages. Differences between patients and healthy controls were tested using the two-tailed t-test. Differences within each group were tested with the paired t-test. The independent sample Student’s t-test was used to compare metabolite concentration in the ACC and basal ganglia between the healthy controls
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Table 1 The clinical and laboratory parameters for the three diagnostic groups. Index
Group I
Group II
Group III
P value
(n = 30)
(n = 29)
(n = 30)
p1
p2
p3
Male/female Age
20/13 48.1 ± 8.2
16/14 45.1 ± 9.5
15/15 44.2 ± 10.5
0.6164 0.1836
0.4530 0.1029
1.000 0.7290
Etiology of liver disease Post-hepatitis Alcoholic Other Albumin(g/L) Prothrombin time(s) International normalized ratio Bilirubin (mol/L) Venous ammonia (mol/L) Child–Pugh score Number connection test A(s) Digit symbol test
15 7 8 37.62 ± 4.80 17.65 ± 3.90 1.65 ± 0.38 43.25 ± 14.60 86.98 ± 25.71 6.5 ± 2.2 65.28 ± 24.69 29.32 ± 12.42
17 8 5 35.58 ± 3.53 16.10 ± 1.84 1.72 ± 0.17 47.40 ± 20.42 75.27 ± 21.55 5.6 ± 3.2 50.15 ± 25.22 48.65 ± 12.11
– – – – – – – – – 39.21 ± 14.52 55.37 ± 13.68
0.3097 0.7686 0.5423 0.0614 0.0517 0.3573 0.3538 0.0559 0.1948 0.0192 <0.0001
– – – – – – – –
– – – – – – – –
<0.0001 <0.0001
0.0440 0.0486
p 1: P value between group I and group II; p 2: P value between group I and group III; p 3: P value between group II and group III.
Table 2 The concentrations of the metabolites (mean ± SD) detected from the 2D MRS peak volumes.
BG (mM)
ACC (mM)
NAA Glu Glna mI Cr NAA Glu Glna mI Cr
Group I
Group II
Group III
P value
(n = 30)
(n = 29)
(n = 30)
p1
p2
p3
8.682 ± 1.218 17.578 ± 3.223 3.875 ± 1.641 3.923 ± 1.595 6.219 ± 1.176 9.327 ± 1.116 17.116 ± 1.715 3.052 ± 1.240 3.821 ± 1.105 6.023 ± 1.295
8.873 ± 1.361 13.489 ± 2.956 3.348 ± 1.516 3.593 ± 1.306 6.447 ± 1.232 9.632 ± 1.682 12.159 ± 1.851 3.412 ± 1.547 3.515 ± 1.207 6.293 ± 1.306
9.242 ± 1.765 8.893 ± 1.272 1.591 ± 1.277 5.827 ± 1.004 6.752 ± 1.163 8.943 ± 1.362 8.451 ± 1.246 1.633 ± 0.748 5.848 ± 1.176 6.477 ± 1.062
0.5719 <0.0001 0.4694 0.3891 0.4700 0.4137 <0.0001 0.5702 0.3138 0.4286
0.1580 <0.0001 0.0153 <0.0001 0.0828 0.2371 <0.0001 0.0343 <0.0001 0.1430
0.3734 <0.0001 0.0400 <0.0001 0.3322 0.0887 <0.0001 0.0342 <0.0001 0.5544
p 1: P value between Group I and Group II; p 2: P value between Group I and Group III; p 3: P value between Group II and Group III. a Gln was detected in 11 patients in group I, 9 patients in group II, and 5 healthy subjects in group III. Cr = creatine; NAA = N-acetyl aspartate; Glu = glutamate; Gln = glutamine; mI = myo-inositol; ACC = anterior cingulate cortex; BG = basal ganglia.
and cirrhotic patients. P-values less than 0.05 were considered statistically significant. 3. Results Four patients (three in group I and one in group II) did not complete the MR examination because of a long scan time. The remaining patients were divided into the following groups: group I (cirrhosis patients with MHE), 30 patients (14 females and 16 males); group II (cirrhosis patients without MHE), 29 patients (14 females and 15 males); and group III (healthy controls), 30 patients (17 females and 13 males). The clinical and laboratory parameters for the three groups are shown in Table 1. The MRS characteristics in the left ACC and left basal ganglia are presented in Table 2. The metabolic changes in the left ACC are described as follows (Fig. 2). There was a significant increase of Glu in the cirrhotic patients (P < 0.001, P < 0.001). A statistical difference was revealed for Glu between patients with and without MHE (P < 0.001). Gln significantly increased in the cirrhotic patients (P = 0.0409, P = 0.0336), but it could not be detected in all cirrhotic patients or the healthy controls. There was a significant decrease in mI for the cirrhotic patients (P = 0.0132, P = 0.0059), but there was no significant difference between the patients with and without MHE (P = 0.7028). There was no significant difference in NAA between the three groups. Our findings indicated elevated Glu in the MHE patients, and decreased mI/Cr in the cirrhotic patients in the left ACC. The findings in the basal ganglia region were similar to the ACC region and the findings for right ROI were similar to the left side.
Fig. 2. Metabolite changes in the ACC for the cirrhotic patients with MHE (group I), the cirrhotic patients without MHE (group II) and the healthy volunteers (group III). *P value < 0.05. Glu significantly increased in the cirrhotic patients, and the difference in Glu was statistically significant in patients with and without MHE. Gln significantly increased in the cirrhotic patients, but it could not be detected in all cirrhotic patients or healthy controls. mI significantly decreased in the cirrhotic patients; however, there was no significant difference between the patients with and without MHE. ACC, anterior cingulate cortex; MHE, minimal hepatic encephalopathy; Glu, glutamate; Gln, glutamine; mI, myo-inositol.
4. Discussion Previous relevant studies have mainly concentrated on the metabolic changes of the brain in cirrhotic patients with clinical HE [8]. The main purpose of this study was to quantitatively study
Please cite this article in press as: L.-p. Meng, et al., Viability assessment of magnetic resonance spectroscopy for the detection of minimal hepatic encephalopathy severity, Eur J Radiol (2015), http://dx.doi.org/10.1016/j.ejrad.2015.06.027
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the brain changes in cirrhotic patients with MHE and cirrhotic without MHE, compared to healthy controls. Furthermore, we used the absolute quantification of the metabolite concentrations (Glu, Gln, mI, NAA and Cr) instead of the metabolic ratios. With the increasing availability of the 3-T MR scanner, the reliability of separating the Glx signals in the brain has improved [12]. In our study, we conducted MRS using a 3-T MR scanner, and found that we were not able to detect Gln in all patients or control subjects; however, an increase in Glu could be detected in all patients with cirrhosis. There was an increase of Glu in patients with cirrhosis, and a significant difference in Glu between patients with and without MHE, which indicated that the increased Glx signal intensity in the brain observed in cases of liver cirrhosis is mainly attributable to an increase in Glu. International society for hepatic encephalopathy and nitrogen metabolism (ISHEN) has suggested to classify HE according to worsening of cognitive function from unimpaired (without any clinical, neurophysiological or neuropsychometric changes) to covert (minimal HE and Grade I according West-Haven) and overt (Grade II according West-Haven) [13]. The patients with MHE are anxious, agitated, have even convulsions and difficulties sleeping, because that Glu is an excitatory neurotransmitter. In the early stage of the disease, in case of hyperammonemia brain participates in conversion of ammonia. High amount of Glu in astrocytes Gln synthetase (GS) transforms into Gln that causes the osmotic disbalance in the cell. Gln is transported to neurons where it is deaminated into Glu by glutaminase. Glu stimulates postsynaptic receptors of neurons [14]. Thus, the difference in Glu levels for patients at the MHE stage can provide an objective measure in the clinical setting. The patients with covert HE are more commonly slower, sleepy, etc. Because of chronic hyperammonemia the mechanisms to keep homeostasis turn on. The amount of Glu receptors in postsynaptic membrane decreases, carriers of Glu are inhibited and less of Glu returns back into astrocytes. High amount of Glu accumulates in the postsynaptic space and suppression of Glu receptors occurs [14]. Moreover, a net increase in inhibitory neurotransmission, due to an imbalance between the functional status of inhibitory (e.g., GABA) and excitatory (e.g., glutamate) neurotransmitter systems [15]. So the level of Glu could not reflect the severity of HE. In this study, we found that Gln concentration increased in the cirrhotic patients, but there was no significant difference between patients with and without MHE. The level of Gln increases in the early stages of MHE; however, the compensatory function of astrocytes can transfer Gln out of the brain [14]. As the disease progresses, Gln quickly increases. Others have reported that Gln increased significantly in the advanced stages of HE [12]. We also found that mI decreased in the cirrhotic patients, but there was no significant difference between the cirrhotic patients with and without MHE. Myo-inositol is an organic osmolyte presumed to act as an astrocyte compensatory tool to buffer an ammonia-induced increase in Gln within astrocytes [16]. However, it takes time to achieve astrocyte volume homeostasis [17]. Minimal hepatic encephalopathy might occur too slightly or too rapidly to allow this compensatory shift. This may explain why there were no significant differences in mI for patients with and without MHE, which indicates that mI might not correlate with the severity of HE. In this study, we used the absolute quantification of the metabolite concentrations instead of the metabolic ratios, which would not be affected by the variability of the internal reference. To express as metabolic ratios, the method for a quantitative analysis requires the use of some references. In brain spectroscopy the total Cr signal has been serving fairly well as an internal reference [18]. However, the concentration of Cr would change in many diseases, such as HE [19]. The results showed that the concentration of Cr was higher in the healthy control group than in the two cirrhosis groups, although these differences did not have the statistical significance. The brain
metabolism changes maybe occurred in the cirrhotic patients and the concentrations of Cr might also change in these patients, thus there would be some bias caused by using the ratios to Cr. Cerebral ammonia metabolism is considered to play a key role in the pathophysiology of HE in patients with acute and chronic liver failure [4,20]. But the “ammonia intoxication hypothesis” cannot fully explain why only some cirrhotic patients went on to develop HE, even though all patients had the same severity of cirrhosis [17]. The ammonia levels correlate poorly with severity of HE [14,21]. In our study, patients with cirrhosis had abnormal venous blood ammonia; while, there were no significant differences in blood ammonia between the cirrhotic patients with and without MHE. Child–Pugh class C cirrhotic patients are likely to develop severe HE [11], so we excluded these patients and only chose the patients with Child-Pugh class A and B. Adequate clinical neuropsychiatric evaluation of these patients remains difficult because neuropsychiatric symptoms associated with low grade encephalopathy are multiform and sometimes subtle. This problem is further exacerbated in the case of MHE, for which patients only demonstrate deficits on neuropsychological tests [5]. Furthermore, these tests can be subject to confounding factors such as age, superimposed mood disorders, and level of education [6]. Therefore, there has been increasing interest in the use of noninvasive imaging techniques, such as magnetic resonance spectroscopy (MRS), to assist in the evaluation of MHE [7]. It has been shown that MHE patients show psychomotor slowing and executive dysfunction, whereas other cognitive abilities are relatively preserved, reflecting a disorder that mainly affects the prefrontal cortex and its connections with the basal ganglia [5,22]. The ACC plays an important role in cognitive functions, such as conflict monitoring, reward anticipation, decision-making, empathy and emotion [11]. In addition, the ACC plays an important role in maintaining the resting state of the brain’s functional network [11]. Thus, the basal ganglia and ACC seem to be appropriate locations to observe functional and metabolite changes in patients with cirrhosis. We acknowledge the following study limitations that may limit the generalization of our results. The comparison of the extent of spectral changes in the ACC and basal ganglia versus other brain regions in cirrhotic patients was not possible in this study because of the scanning time. Other studies comparing spectral changes in the occipital, frontal and parietal lobes have showed heterogeneous results [3,23]. Whether more significant spectral changes are seen in the ACC and basal ganglia compared to other brain regions in cirrhotic patients deserves further investigation. In summary, we found that MRS using a 3-T MR scanner could be used to detect cerebral metabolic changes in cirrhotic patients with MHE. The typical MRS brain characteristic in these patients was elevated Glu, which could be used as a sensitive indicator to evaluate the MHE severity in patients with cirrhosis.
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