Neuroradiology (2014) 56:885–891

DOI 10.1007/s00234-014-1409-0

PAEDIATRIC NEURORADIOLOGY

Minimal hepatic encephalopathy in children with liver cirrhosis:

diffusion-weighted MR imaging and proton MR spectroscopy
of the brain
Ahmed Abdel Khalek Abdel Razek & Ahmed Abdalla &
Amany Ezzat & Ahmed Megahed & Tarek Barakat

Received: 11 April 2014 / Accepted: 16 July 2014 / Published online: 25 July 2014
# Springer-Verlag Berlin Heidelberg 2014

Abstract Conclusion DWI and 1H-MRS are imaging modalities that

Introduction The aim of this work was to detect minimal can detect minHE in children with liver cirrhosis and correlate
hepatic encephalopathy (minHE) in children with diffusion- well with parameters of NPT.
weighted MR imaging (DWI) and proton magnetic resonance
spectroscopy (1H-MRS) of the brain. Keywords Hepatic . Encephalopathy . Children . Diffusion .
Methods Prospective study conducted upon 30 consecutive MR spectroscopy
children (age range 6–16 years, 21 boys and 9 girls) with liver
cirrhosis and 15 age- and sex-matched healthy control chil-
Abbreviations
dren. Patients with minHE (n=17) and with no minHE
Cho Choline
(n=13) groups and control group underwent DWI, 1H-
Cr Creatine
MRS, and neuropsychological tests (NPTs). The gluta-
DWI Diffusion-weighted MR imaging
mate or glutamine (Glx), myoinositol (mI), choline
HE Hepatic encephalopathy
(Cho), and creatine (Cr) at the right ganglionic region were
mI Myoinositol
determined at 1H-MRS. The apparent diffusion coefficient
minHE Minimal hepatic encephalopathy
(ADC) value and metabolic ratios of Glx/Cr, mI/Cr, and
NAA N-acetylaspartate
Cho/Cr were calculated.
NPT Neuropsychological tests
Results There was elevated ADC value and Glx/Cr and de-
OHE Overt hepatic encephalopathy
creased mI/CI and Ch/Cr in patients with minHE compared to
H-MRS Proton magnetic resonance spectroscopy
no minHE and control group. There was significant difference
Glx Glutamate or glutamine
between minHE, no minHE, and control group in the ADC
IQ Intelligence quotient
value (P=0.001 for all groups), GLx/Cr (P=0.001 for all
groups), mI/Cr (P=0.004, 0.001, and 0.001, respectively),
Ch/Cr (P=0.001 for all groups), and full-scale IQ of NPT
(P =0.001, 0.001, and 0.143, respectively). The NPT of Introduction
minHE had negative correlation with ADC value (r=−0.872,
P=0.001) and GLx/Cr (r=−0.812, P=0.001) and positive Minimal hepatic encephalopathy (minHE) is a subclinical
correlation with mI/Cr (r=0.732, P=0.001). complication of liver cirrhosis in which the patients have
subtle cognitive and psychomotor disturbances that are not
obvious at neurological examination and detected at neuro-
A. A. K. A. Razek (*) : A. Ezzat
psychological test (NPT). The minHE found in up to 70 % of
Department of Diagnostic Radiology, Mansoura Faculty of adult cirrhotic patients. The incidence of minHE in children
Medicine, Mansoura University Hospital, Mansoura 13551, Egypt with liver cirrhosis is still unknown [1–7]. Early diagnosis and
e-mail: arazek@mans.edu.eg treatment of minHE in children is important for the preserva-
A. Abdalla : A. Megahed : T. Barakat
tion of brain function in which brain experiencing maturation
Gastroenterology and Hepatology Unit, Mansoura Faculty of and cognitive development as well as about 50 % of cirrhotic
Medicine, Mansoura Children Hospital, Mansoura, Egypt children with minHE present with overt HE (OHE) after
886
3 years as opposed to 8 % of the patients without minHE
[2–4]. In addition, abnormal cognitive functions interfere
significantly with the daily activities. Early detection of
minHE may be helpful in mitigating the neurocognitive de-
clines seen in children with liver disease by consideration of
liver transplantation before obvious end-stage liver disease
[8–11].
MinHE characterized by mild cognitive and psychomotor
deficits that detected with NPT [6–10]. There is a consensus
and standardization in using the NPT battery to assess the
presence of minHE [2–5]. Abnormal NPT is sufficient to
establish diagnosis of minHE. However, the tests are not
specific and affected by patient age, anxiety, mood disorders,
educational effects, and linguistic abilities [13–16]. Magnetic
resonance (MR) imaging studies [17–22] including proton
magnetic resonance spectroscopy spectroscopy (1H-MRS)
[23–30], magnetization transfer ratios [31], voxel-based mor-
phometry [32], and diffusion tensor imaging [33–37] have
been used to understand cerebral alterations of hepatic en-
cephalopathy (HE). There are few studies that discuss the role
of MR imaging in children with minHE [8], HE with extra-
hepatic portal vein obstruction [9–11], and acute liver failure
[38].
The aim of this work was to detect minHE in children with
DWI and 1H-MRS and to correlate DWI and 1H-MRS find-
ings with NPT results.
Material and methods
Patient selection
Prospective study conducted upon 40 consecutive children
with liver cirrhosis. Ten patients were excluded from the study
due to OHE (n=7) and recent gastrointestinal bleeding (n=3).
The final included patients were 30 children with age range,
6–16 years; mean age was 12.5 years, 21 boys/9 girls. All
patients had established liver cirrhosis that diagnosed at liver
biopsy. The causes of cirrhosis were autoimmune hepatitis
(n=22), viral hepatitis (n=3), alpha one antitrypsin deficiency
(n = 3), and cryptogenic (n = 2). Fifteen age-, sex-, and
education-matched healthy children (with age range, 7–
15 years; mean age was 11 years, 10 boys/5 girls) were
included as controls. The mean number of education years
of patients was 7.2 years and of controls was 6.9 years. All
patients and controls underwent NPT, conventional MR,
DWI, and 1H-MRS of the brain. The study protocol conforms
to the ethical guidelines of the 1975 Declaration of Helsinki as
reflected in a priori approval by the institution’s human re-
search committee. Approval of ethics committee was obtained
and informed consent obtained from legal guardian of chil-
dren and controls before they participated in the study.
Neuroradiology (2014) 56:885–891
Neuropsychological test
The NPT was done using well-established Egyptian version of
Wechsler intelligence tests. These tests were quoted from the
original version of Wechsler Intelligence Scale for Children-
III (WISC-III) [39]. The test battery includes six verbal sub-
tests (information, digit span, vocabulary, arithmetic, compre-
hension, and similarity) and six performance subtests (pic-
ture completion, picture arrangement, block design, object
assembly, digit symbol, and symbol search). Individual
subtests scaled scores; verbal IQ, performance IQ, and
full-scale IQ were the parameters of interest. The time
taken for completing the NP test battery ranged from 35
to 45 min. Test scores considered abnormal if patients’
values lay beyond mean±2 SD, from normal established
in age-, gender-, and education-matched healthy controls.
MinHE diagnosed if ≥2NPTs were abnormal. Based on
NP test results, patients grouped into minHE and no
minHE [33].
Conventional magnetic resonance imaging
MR imaging performed using a 1.5-Tesla scanner equipped
with echoplanar capabilities (Symphony, Siemens, Erlangen,
Germany). The machine was equipped with a self-shielding
gradient set (30 mT/m maximum gradient strength and 120 T/
m/s slew rate) and a commercially available circularly polar-
ized head coil. MR imaging consisted of transverse T1- and
T2-weighted imaging. The imaging parameters were TR/TE=
500/14 ms for T1-weighted images and 5,000/86 ms for T2-
weighted images, field of view (FOV)=240×240 mm, section
thickness=5 mm, and intersection gap=0.5 mm. The brain
MR imaging was reviewed to exclude other pathologic
processes.
Diffusion magnetic resonance imaging
Diffusion-weighted MR imaging conducted by using single-
shot spin-echo echoplanar imaging. The diffusion-weighting
gradients were applied on each of the three physical axes x, y,
and z with b factor values of 0, 500, and 1,000 mm2/s. The
scanning parameters were TR/TE=4,000/100 ms, number of
averages=1, FOV=240×240 mm, slice thickness=5 mm,
interslice gap=0.5 mm, and matrix=96×128 pixels. After
application of diffusion-weighted sequence, we obtained a
set of images corresponding to each b value applied. The
apparent diffusion coefficient (ADC) map automatically was
calculated from the data set obtained at three b values by
commercially available software (Leonardo, version 2.0;
Siemens AG Medical systems, Forchheim, Germany). The
data acquisition time for the diffusion-weighted MR images
was 1 min. The mean ADC was determined in manually
drawn regions of interest placed in the right basal ganglia.
Neuroradiology (2014) 56:885–891
The ADC value was calculated according to the following
formula: ADC_−(lnSb2−lnSb1)/(b2−b1), where ln is the
natural log, and Sb1 and Sb2 are the signal intensities in the
ROI placed on sections corresponding to the two different b
values (b1 and b2) [40, 41]. The ADC value automatically
calculated in 10–3 mm2/s.
Proton magnetic resonance spectroscopy
The homogeneity of the magnetic field over the volume of
interest was optimized by shimming. Suppression of the water
signal was performed by using three preceding Gaussian
pulses (60-Hz bandwidth). Single voxel point-resolved spec-
troscopy pulse sequence (PRESS) technique (Fig. 1) was
applied using the following parameters: TR/ TE =1,500/
35 ms, voxel size=8 cm3, and number of averages=128.
Voxel of 2×2×2 cm3was located in the right basal ganglia
according to previous study [9]. A standard software package
(Syngo; Siemens) was used for postprocessing MR spectro-
scopic data. The peaks fitted included 3.75 ppm for glutamate
or glutamine (Glx), 3.5 ppm for myoinositol (mI), 3.22 ppm
for choline (Cho), 3.03 ppm for creatine (Cr), and 2.00 ppm
for N-acetylaspartate (NAA). By using standardized
postprocessing protocols, the raw data processed automatical-
ly, allowing for operator-independent quantifications. To min-
imize the amount of arbitrary operator input, no use was made
Fig. 1 Localization for 1H-MRS. Axial T2-weighted image shows that
the voxel of interest is located in the right basal ganglion region
887
of the possibility of retrospective voxel shifting. The integrals
of Glx, mI, Cho, and Cr were calculated. The ratios of inte-
grals of various metabolites calculated with respect to Cr
included Glx/Cr, mI/Cr, Cho/Cr, and NAA/Cr.
Statistical analysis
The statistical analysis of data was done by using Statistical
Package for Social Science version 16.0 (SPSS Inc., Chicago,
IL, USA). The Kolmogorov-Smirnov (K-S) test was done for
diagnosis normality of data distribution. All data were para-
metric with normal distribution. The mean and standard devi-
ation (SD) of the ADC; Glx/Cr, mI/Cr, and Cho/Cr of MRS;
and verbal IQ, performance IQ, and full-scale IQ of NPTs
were calculated. The analysis of data was done to test statis-
tical significant difference. Independent sample (student t test)
and one-way ANOVA were done to study the difference of the
ADC values, metabolites ratios, verbal IQ, performance IQ,
and full-scale IQ of NPTs between patient groups (minHE, no
minHE) and control group. Pearson correlation test was used
to correlate the ADC value and metabolic ratios of minHE
with full-scale IQ. The correlation coefficients r and P value
were calculated. The P value was considered significant if
≤0.05 at confidence interval of 95 %.
Results
Among the 30 patients with liver cirrhosis included in this
study, minHE was detected in 17 patients (56.7 %) and was
absent in 13 (43.3 %; no minHE group) based on NPT results.
Table 1 shows the ADC value, MRS metabolite ratios, and
NPT in minHE, no minHE, and control groups.
Neuropsychological test
At NPT, both verbal IQ and performance IQ were significantly
different in minHE group compared with healthy controls (P=
0.001, respectively), with consecutive affection of the full-
scale IQ (P=0.001) while the no CHE group was insignifi-
cantly affected regarding verbal IQ, performance IQ, and full-
scale IQ (P=0.988, P=0.070, and P=0.143, respectively)
compared with healthy controls.
The full-scale IQ had negative correlation with ADC value
(r=−0.872, P=0.001) and GLx/Cr (r=−0.812, P=0.001) and
positive correlation with mI/Cr (r=0.732, P=0.001).
Conventional and diffusion magnetic resonance imaging
There are no areas of abnormal signal intensity that could be
detected at T1- and T2-weighted images. The mean ADC
value of the right basal ganglion in cirrhotic patients with
minHE was 87.58±2.3×10−3 mm2/s, in patients with no
888 Neuroradiology (2014) 56:885–891

Table 1 The mean and standard deviation of ADC value, MRS metabolites, and NPT in minHE, no minHE, and control groups

minHE group No minHE group Control group P value

(n=17) (n=13) (n=15)
a b c

ADC (10−3 mm2/s) 87.58±2.30 73.66±2.02 69.65±2.28 0.001 0.001 0.001

MRS
Glx/Cr 2.85±0.40 2.14±0.44 1.69±0.37 0.001 0.001 0.001
mI/Cr 0.30±0.08 0.48±0.12 0.60±0.24 0.004 0.001 0.001
Cho/Cr 0.62±0.05 0.71±0.04 0.85±0.02 0.001 0.001 0.001
NAA/Cr 2.54±0.43 2.62±0.32 2.75±0.15 0.886 0.535 0.659
NPT
Verbal IQ 94.24±8.4 108.69±6.05 108.73±5.56 0.001 0.001 0.988
Performance IQ 78.06±10.8 88.76±12.09 95.40±2.67 0.004 0.001 0.070
Full-scale IQ 85.47±9.5 98.62±6.09 102.60±3.73 0.001 0.001 0.143

a minHE versus no minHE, b minHE versus control, c no minHE versus control

minHE was 73.66±2.020×10−3 mm2/s, and in the control
group was 69.65±2.28×10−3 mm2/s. The ADC values were
significantly higher in minHE group compared to no minHE
(P=0.001) and control groups (P=0.001).
Proton magnetic resonance spectroscopy
At 1H-MRS, the Glx/Cr was higher in patients with minHE
and no minHE than control group. On the other hand, the mI/
Cr and Cho/Cr were lower in patients with minHE and no
minHE than control group (Fig. 2). There was no significant
difference in NAA/Cr between patients with minHE and no
minHE. There was significant different between minHE ver-
sus no minHE, minHE versus control, and no minHE versus
control in Glx/Cr (P=0.001, 0.001, and 0.001, respectively)
and significant decrease in mI/Cr (P=0.001, 0.004, and 0.001,
respectively) and Cho/Cr (P=0.001, 0.001, and 0.001, respec-
tively) (Table 1).
Discussion
The pathophysiology of HE remains incompletely defined. At
least three elements are reported to contribute to the patho-
physiology of HE: (1) neurotransmission abnormality, (2)
neuroinflammation (microglia activation), and (3) astrocytic
injury. Neurotransmission abnormalities are caused by an
imbalance between the inhibitory and excitatory neurotrans-
mission systems toward an increase of the inhibitory system
with an increase in intra-astrocytic glutamine due to the high
ammonia levels. Neuroinflammation in HE is characterized
by microglial activation with local brain production and re-
lease of proinflammatory cytokines including TNF-α and
interleukins IL-1b and IL-6. The most recent theory of how
astrocytic swelling occurs includes “Trojan horse” hypothesis
of glutamine being carried into mitochondria causing oxida-
tive stress and microglial activation, which also contributes to
oxidative stress [20, 24, 42, 43].
In the present study, there is significantly higher ADC in
patients with minHE compared to patients with no minHE and
control groups, which is associated with poor NPT score due
to extracellular accumulation of water in chronic liver failure.
Plausible explanation is extracellular migration of mac-
romolecules induced by increase astrocytic glutamate or
increase blood-brain barrier permeability. In addition,
hyperammonemia may increase blood-brain barrier per-
meability that leads to capillary water influx to the brain
[20–24]. Several studies reported that ADC/mean diffu-
sivity is reliable tool for quantification of low-grade
edema in patients with minHE, as mean diffusivity
increases in patients with minHE compared with con-
trols. In addition, the mean diffusivity correlates with
grades of HE, NPT scores, and 1H-MRS biomarkers in
patients with chronic liver failure [33–37]. One study re-
ported that cerebral edema is more extensive, involving the
cortical and deep gray matter as well as deep white matter,
in minHE than in no minHE in adults [33]. Other study
added that regional difference of ADC/diffusivity in pa-
tients with minHE and proposed that higher diffusivity of
frontal and parietal white matter can predict further bouts of
OHE [34].
These implications applied to chronic liver failure patients
and not to acute or OHE patients due to time-dependent
compensatory mechanism. The significance of ADC and dif-
fusivity being high or low varies according to the clinical stage
and acuity of the disease. High ADC in chronic liver failure
patient may be a sign of worsening disease, while a rapid
decrease in ADC in acute liver failure patients due to acute
cellular injury is a poor harbinger [18–20, 24].
Neuroradiology (2014) 56:885–891
Fig. 2 1H-MRS of the brain in children with minHE (a), no minHE (b), and control (c). Child with minHE (a) shows higher Glx/Cr and lower Cho/Cr
and mI/Cr compared to no minHE (b) and control child (c)
1
H-MRS used for assessment of diffuse metabolic disease
of the brain [44]. 1H-MRS studies provided evidence for the
presence of an osmoregulatory mechanism in patients with
cirrhosis with HE and chronic hyperammonemia in the form
of depletion of the mI peak and elevation of the Glx peak in
children [8–11] and adults [10–13]. A characteristic triad of
increased glutamine with decreased mI and Cho seen on brain
1
H-MRS considered the hallmark of hepatic dysfunction.
These metabolite abnormalities are reversible after liver trans-
plantation [23–30].
In this study, there was statistically significant in-
crease in Glx/Cr ratio and reduction in mI/Cr and
Cho/Cr ratios and insignificant difference in NAA/Cr
ratio in patients with minHE group compared to patients
with no minHE and control groups. The increase in
Glx/Cr reflects increased glutamine concentration in
the brain, a finding that attributed to increased detoxi-
fication of ammonia by astrocytes into glutamine via the
amidation of glutamate [23–26]. In addition, in patients
with cirrhosis with or without HE, a low level of mI
has been reported because there is an increase in intra-
cellular osmolality secondary to accumulation of gluta-
mine that compensated by a decrease in intra-cellular mI
[25–27]. Lastly, the Cho reduction in patients with liver
cirrhosis is likely to reflect alterations in phospholipid
metabolism and membrane fluidity because
glycerophosphorylcholine is itself a cerebral osmolyte
[26–30]. However, a normal Cho/Cr ratio was reported in
children with extrahepatic portal venous obstruction and cir-
rhosis with or without HE [9].
The NPTs are of value for evaluating and quantifying
cognitive impairment in patients with minHE. These tools
allow better evaluation of the origin of cognitive complaints
and help in estimating the risk of accidents [3–6]. These tests
are a valid test for diagnosis of minHE, as they directly
measure cognitive functions that are directly relevant to activ-
ities of daily living. However, these tests are associated with
subjectivity of the individuals involved in their assessment
889
[13–15]. The NPTs tend to significantly correlated with
functional status [14–16]. In this study, the NPT well
correlated with ADC value and metabolic change,
denoting that cerebral brain edema and altered metabolic
changes were responsible for abnormalities in NPTs in
these patients.
There are few limitations of this work. First, we applied
diffusion-weighted MR imaging. Further studies with appli-
cation of diffusion tensor MR imaging and new post process-
ing methods such as non-Gaussian (diffusion kurtosis) model-
ing or K-means clustering algorithms will improve the results
with global assessment of diffusivity of the brain [45, 46].
Second, we applied single voxel study of basal ganglion at
short TE (35 ms) for better assessment of some metabolites
such as glutamate or glutamine (Glx) and mI. However,
further studies done at 3-Tesla scanner using multivoxel
chemical shift imaging at high (270 ms) and intermediate
(135 ms) with application of advanced postprocessing and
quantitative assessment of metabolites will improve the results
and allow detection of subtypes of glutamate. Third, there is
no follow-up of these patients after therapy or prognosis for
longitudinal studies.
Conclusion
We concluded that DWI and 1H-MRS are imaging modalities
that can detect minHE of the children with cirrhosis and
correlate well with parameters of NPT.
Ethical standards and patient consent We declare that all human
studies have been approved by the local ethics committee and have
therefore been performed in accordance with the ethical standards laid
down in the 1964 Declaration of Helsinki and its later amendments. We
declare that all patients gave informed consent prior to inclusion in this
study.
Conflict of interest We declare that we have no conflict of interest.
890
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