Comparison of diffusion kurtosis imaging and diffusion weighted imaging in

differentiation liver fibrosis at early stage and inflammatory activity from normal liver
Purpose
To compare the diagnostic value of mean apparent diffusion (MD), mean kurtosis (MK) and
apparent diffusion coefficient (ADC) of liver parenchyma in differentiation liver fibrosis at
early stage and inflammatory activity from normal liver.
Methods
20 patients with pathologically provedn liver fibrosis at the early stage and inflammatory
activity and 20 with healthy livers underwent a 3.0 T MRI examination, including DKI with 4
b-values (0, 1000, 1500, and 2000 s/mm2) and DWI with 2 b-values (0 and 800 s/mm2). MD,
MK and ADC of liver parenchyma were compared among groups of with normal and fibrosis
liver at different stages using One-way of variance, between normal and patients with
inflammatory activity using Student t test, and correlated with fibrosis stages and
inflammatory activity using Spearmans rank correlation test. Quantitative parameters derived
from DKI and DWI for predicting liver fibrosis at early stage or inflammatory activity was
evaluated using Receiver operating characteristic curve (ROC) analysis.
Results
MD decreased significantly in mild fibrosis (F1) and moderate fibrosis (F2) compared with
that in normal group (P < 0.001). MD decreased significantly in patients with inflammatory
activity compared with to that in the normal group (P < 0.001). MD had moderate correlation
with fibrosis stages (r = -0.623, P < 0.001) and inflammatory activity (r = -0.635, P < 0.001).
When the optimal cutoff value of 1.7 10 -3 mm2/s were used, the AUC of 0.867 (95% CI
0.723-0.953, P < 0.001), sensitivity of 80% and specificity of 90% in MD can be achieved for
predicting liver fibrosis at early stage or inflammatory activity. MK and ADC were not
statistically significantly different significant among groups of normal and fibrosis at
different stages (P > 0.05), between normal and patients with inflammatory activity, and had
no correlation with fibrosis stages and inflammatory activity (P > 0.05).
Conclusion
MD can be reliable to do differentiation liver fibrosis at early stage and inflammatory activity
from normal liver and can serve as a valuable tool for predicting liver fibrosis and
inflammatory activity.
Key words: liver; fibrosis; inflammatory activity; early stage; kurtosis; diffusion

Introduction
Liver fibrosis is a common pathology that occurs in almost all most of the cases of chronic
liver disease. Left untreated, it can progress to cirrhosis, which substantially increases the risk
[1-2]
for the occurrence of hepatocellular carcinoma . Originally considered to be irreversible,
 [2-3]
hepatic fibrosis is now regarded as a dynamic process with the potential for regression .
Thus, early and accurate detection of liver fibrosis is of the uttermost important importance
for the clinical treatment. Liver biopsy is currently the standard of reference for the diagnosis
and staging of liver fibrosis. However, it is an invasive technique and is associated with
complication such as pain and bleeding. Further, liver biopsy covers only a small part of the
liver, and there is the possibility of sampling error [4-5].
Currently, many noninvasive methods were attempted to assess liver fibrosis, such as serum
markers and many imaging techniques. However, serum markers might be influenced by
many factors and the specificity is low [6]. Transient elastography (TE) could be widely used
as a good screening test for cirrhosis in clinical practice, with 90% probability of correctly
diagnosing cirrhosis, but only 78-85% of correctly diagnosing low grade fibrosis, and limited
to steatitis, inflammation, and patients who are obese or who have narrow intercoastal spaces
and ascites [7-9]. Perfusion CT could be used to detect microcirculatory changes in cirrhosis and
help to differentiate low grade fibrosis [10-11], but radiation, the use of contrast agents and scan
coverage range make it impossible to be widely used [12]. Liver specific contrast enhanced
magnetic resonance imaging (MRI) could be used to measure hepatocyte function. The
enhancement degree and heterogeneity of liver parenchyma on hepatocyte phase is correlated
with the degree of liver fibrosis, but limited to the use of contrast agents and long examination
time [13-15]. Although limited by high iron overload, portal hypertension, inflammatory activity
and the need for dedicated equipment installation, Mmagnetic resonance elastography has
been established as an accurate method for the detection and stratification of liver fibrosis
with accuracy more than 0.9[9-10], but limited with high iron overload, portal hypertension,
inflammatory activity and the need for dedicated installation equipment [16-19]. Diffusion
weighted MRI (DWI) can detect changes of water diffusion, and had moderate diagnostic
accuracy for assessing liver fibrosis, but cant distinguish each stages of fibrosis [20].
Diffusion kurtosis imaging (DKI) is an advanced DWI model that quantifies the non-
Gaussian behavior of diffusion by using high b-values and kurtosis analysis. Previous studies
of DKI in animal models have reported the possibility of staging liver fibrosis, and better
[21-22]
diagnostic performance than conventional DWI , but to the best of our knowledge, no
study has been reported on clinical patient with liver fibrosis. In addition, diagnostic
performance of DKI for liver fibrosis was only evaluated to differentiate mild and moderate
(F1-2) fibrosis from advanced fibrosis (F3-4), or differentiate from non-cirrhosis (F1-3) from
cirrhosis (F4) [21]. More studies are needed to investigate the discriminative ability of DKI for
liver fibrosis in early stage. Therefore, the purpose of this study was to compare the
diagnostic value of mean apparent diffusion (MD), mean kurtosis (MK) and apparent
diffusion coefficient (ADC) of liver parenchyma in differentiation liver fibrosis at early stage
and inflammatory activity from normal liver.
Materials and Methods
Subjects
This prospective study was approved by our institutional review board and waived the
required for informed patient consent.
From January 2015 to December 2016, a total of 67 patients underwent abdominal MRI
including DWI with 2 b-values and DKI with 4 b-values. The inclusion criteria for this study
were: 1) no contraindications to MR imaging; 2) available DWI and DKI imaging data; 3) no
alcohol abuse (< 20 g/day in men; < 10 g/day in women). Among them, 27 patients were
excluded, one because of multiple liver cyst, two because of fatty liver identified by T1 in-
opp images, 24 with hepatitis virus infection because of lacking pathological results.
The remaining 40 study subjects were finally included in our study population. The control
group included 20 patients (13 men, 7 women; mean age, 40.2 years; range, 2746 years)
whose laboratory, ultrasound and magnetic resonance imaging exams demonstrated liver's
normal conditions. For ethical reasons, these patients did not undergo liver biopsy. The
fibrosis group included 20 patients (14 men, 6 women; mean age, 38.7 years; age range, 27
50 years) with histopathologic findings as the reference standard.
Histopathologic analysis
An US-guided percutaneous liver biopsy of the right lobe was performed within 3 days
following MRI. An experienced hepatic pathologist (J.L with 5 years of experience in liver
pathology) who was blinded to the imaging findings reviewed the liver specimen and staged
the extent of the fibrosis and inflammatory activity using the Batts and Ludwig scoring
system (F0, no fibrosis, F1 indicated portal fibrosis, F2, periportal fibrosis, F3, septal fibrosis,
F4, cirrhosis; G0, no activity; G1, minimal inflammation; G2, mild inflammation; G3, moderate
inflammation; G4, severe inflammation) [23].
MR examination
MRI was performed on a 3.0T MRI system (Ingenia; Philips Healthcare, Best, the
Netherlands) with a 36-channel torso coil. Respiratory triggering (respiratory belt) was used
to minimize respiratory motion artifacts, which allowed the patient to breathe freely during
image acquisition in the supine position. Volume shimming was used to minimize B0
inhomogeneity.
All the images were acquired using a respiratory-triggered fat-suppressed single-shot echo-
planar sequence. The imaging parameters were as follows: TR/TE, 2000/67 ms; section
thickness, 6 mm; no intersection gap; FOV, 380 mm 304 mm; matrix, 256 256; parallel
imaging factor, 2.2; DKI with b-value of 0, 1000, 1500, and 2000 s/mm 2; DWI with b-value
of 0 and 800 s/mm2; Acquisition time for DKI, approximately 10 min; Acquisition time for
DWI, approximately 2 min.
Image analysis
DKI data was quantitatively analyzed according to kurtosis model and DWI data was
quantitatively analyzed according to mono-exponential model using post-processing software
performed in a proprietary programming environment (PRIDE; Philips Medical Systems,
Best, The Netherlands).
For the kurtosis model, the mean diffusion (MD) and mean kurtosis (MK) were calculated by
kurtosis fitting of 4 b-values on a pixel-by-pixel basis according to the following equation:
SI = SI0exp (-bD + b2D2K/4),
Where b is the b value, D is the corrected ADC accounting for non-Gaussian behavior, and K
is excess kurtosis.
For the mono-exponential model, the apparent diffusion coefficient (ADC) was calculated by
mono-exponential fitting of 2 b-values on a pixel-by-pixel basis according to the following
equation:
SI = SI0 exp (-bADC),
Where SI is the signal intensity at a given b value and SI 0 is the signal intensity for b = 0
s/mm2.
Two radiologists (SS.X with 4 and Y.C with 11 years of experience in abdominal imaging)
performed quantitative image analysis in a blinded manner. The readers were blinded to the
group of patients and pathological results. The upper, middle and lower liver slices were
chosen, and six ROIs were positioned in the right liver lobe, four were positioned in the left
liver lobe to measure the MD, MK and ADC of liver parenchyma, avoiding large vessels,
lesions, artifacts, and the border of the liver. The location and size of each ROI were kept as
same as possible in different parametric maps (Figure 1). The mean size of all ROIs was 25
pixels 2, with a range from 20 to 28 pixels. The mean values of MD, MK and ADC were
obtained by averaging all ROIs measurement.
Statistical analysis
The one-sample Kolmogorov-Smirnov test was used to test the normal distribution of
quantitative variables. When the quantitative variables were normally distributed, the results
were expressed as mean values and standard deviations; otherwise, medians and interquartile
ranges (25th-75th percentile) were reported; Qualitative variables were summarized as counts
and percentages. The age and body mass index were compared between normal subjects and
patients with early fibrosis using the Student t test. The sex distribution was compared using
Chi-square test. The MD, MK and ADC were compared among different fibrotic stages using
One-way of variance (ANOVA), and followed by least-significant difference (LSD) post-hoc
testing when indicated. The MD, MK and ADC were compared between normal subjects and
patients with inflammatory activity using Student t test. The correlation between fibrosis
stages or inflammatory activity and quantitative parameters were analyzed using Spearmans
rank correlation test. The accuracy of quantitative parameters for assessing liver fibrosis at
early stage or inflammatory activity was evaluated by calculating sensitivity, specificity and
receiver operating characteristic (ROC) curves. The interobserver reproducibility of each
imaging parameter was assessed by calculating the intraclass correlation coefficient (ICC).
All statistical tests were two sided, and a P value of 0.05 or less was considered to indicate a
significant difference. Statistical analyses were performed using the SPSS software for
Windows, version 13.0 (SPSS, IL, USA) and Medcalc (version 11.2; 2011 MedCalc Software
bvba, Mariakerke, Belgium).

Results
Patient demographics, etiology of liver disease and histopathological data
Patient demographics and histopathological assessment of hepatic fibrosis stage and
inflammatory activity observed among the forty subjects are summarized in Table 1. The
etiology of all patients in fibrosis group was hepatitis B virus infection. The pathological
results of all patients demonstrated no steatosis in hepatocytes and iron load.
Diffusion parameters and fibrosis stage
The ICC for interobserver reproducibility of MD, MK and ADC were 0.894, 0.908 and 0.923,
respectively.
For relatively small number of F3, multivariable comparisons were made for F0 vs. F1, F1 vs.
F2 and F0 vs. F2. Distribution and comparison of MD, MK and ADC in patients with
different fibrosis stages is shown in Table 2. MD decreased as the increasing of fibrosis stage
and showed significant difference between F0 vs. F1 and F0 vs. F2 (P < 0.05, Figure 2).
Moderate inverse correlation was found between fibrosis stages and MD (r = -0.623, P <
0.001; Figure 3). MK and ADC showed no marked trend in the early stages of liver fibrosis
and were not significantly different among all groups (P > 0.05). No correlation existed in
MK and ADC (P > 0.05).
Diffusion parameters and inflammatory activity
Distribution of MD, MK and ADC in patients with different inflammatory activity is shown in
Table 3. MD decreased as the increasing of inflammatory activity and showed significant
difference between normal and patients with inflammatory activity (1.75 0.09 vs. 1.60
0.13, t = 4.671, P < 0.001). Moderate inverse correlation was found between inflammatory
activity and MD (r = -0.635, P < 0.001; Figure 4). MD was significantly different between
normal and patients with inflammatory activity. MK and ADC showed no significant
differences between the two groups (MK: 0.74 0.06 vs. 0.73 0.06, t = 0.193, P = 0.848;
ADC: 1.28 0.09 vs. 1.20 0.16, t = 2.097, P = 0.058). No correlation existed in MK and
ADC (P > 0.05).
ROC analysis
ROC analyses demonstrated AUCs of 0.867 (95% CI 0.723-0.953, P < 0.001) in MD for the
identification of liver fibrosis at early stage (F1-3) or inflammatory activity. When the optimal
cutoff values of 1.7 10-3 mm2/s were used, the sensitivity of 80% and specificity of 90% can
be achieved.

Discussion
Liver fibrosis, especially at early stage, can be treatable and reversible [2-3]. So, patients with
early fibrosis (F1-3) were selected and compared with normal subjects in this study. We have
got two important results. The first one is that MD decreased as the increasing of fibrosis
stage and correlated with fibrosis stages moderately. So, MD can be used to predict liver
fibrosis at early stage accurately. The second one is that MD decreased as the increasing of
inflammatory activity and correlated with inflammatory activity moderately. So, MD can be
used to predict liver inflammatory activity at the same time.
Both MD derived from DKI and ADC derived from conventional DWI can reveal the
[24-25]
diffusivity of water molecules in tissue . In this study, MD decreased significantly in
patients with mild fibrosis (F1) or moderate fibrosis (F2) when compared with normal liver
(F0), and had a good diagnostic efficiency for early fibrosis. This promises the ability of MD
in DKI in discrimination of normal and liver fibrosis at early stage. However, this study
showed ADC decreased with the progression of liver fibrosis, but no significant difference
was found. A possible explanation could be that conventional DWI enables the visualization
of diffusivity of water molecules, but the model is calculated using a mono-exponential
[26]
analysis and assumes Gaussian behavior of water diffusion . However, within biological
tissues, the movement and distribution of water molecules are restricted because of the
presence of microstructures, and this may be more obvious in fibrotic liver. DKI provides a
new model in assessing non-Gaussian behavior, and MD reflected the diffusion of water
[27-28]
molecules which was corrected accounting for non-Gaussian diffusion behavior . Thus,
MD in DKI may have better performance than ADC in detecting liver fibrosis at early stage.
In addition, this study showed MD had a moderate correlation and ADC had no correlation
with fibrosis stages. The trend of MD was lower but consistent with animal studies by Sheng
et al [21] and Anderson et al [22], but ADC was not consistent with previous studies. A possible
explanation for the discrepancy may be due to the differences of study objects. In our study,
only patients with early fibrosis (F1-3) were recruited, and the number of patients in F3 was
small. While, the animal study recruited all fibrosis stages (F1-4) and the number of each
stage was similar. In this study, MD also decreased significantly in patients with inflammatory
activity (G1-3) compared with normal liver (G0g) and correlated with inflammatory activity
[21-22]
moderately, which was consistent with animal studies . This promises that MD in DKI
may also have the ability in discrimination inflammatory activity in liver fibrosis.
In theory, MK reflects the tissue complexity [24-25, 28-29]. In this study, MK showed no significant
differences between patients with fibrosis and normal subjects, which coincided with animal
study by Sheng et al [21]. This promises none discrimination capacity of MK in early fibrosis.
In addition, Goshima et al [25] compared MK among different Child-Pugh grades, Kartalis et al
[30] [31]
compared MK between tumorous and non-tumorous of pancreatic cancer, and Yu et al
compared the MK between good responder group and poor responder group to treatment in
locally advanced rectal cancer, but all of the above found negative results. So, a possible
explanation may be that MK was unaffected by microstructural changes when applied to
clinical diseases. However, Anderson et al [22] found strong correlation between fibrosis stages
and hepatic MK on liver specimens ex vivo, Goshima et al [25] found MK was significantly
higher for the viable group than for the nonviable group to treatment in hepatocellular
carcinoma, Dai et al[32] found MK was significantly different between different grade of clear
renal cell carcinoma, and Tamura et al [33] found MK was significantly higher in prostate
cancer and stromal benign prostatic hyperplasia than in benign peripheral zone. Those were
contrary to our result. So the other possible explanation of our study could be that
microstructural complexity in early fibrosis changed too slight, which was not enough to
change MK value of liver parenchyma. So, further studies are needed to confirm the most
possible explanation of MK in our study and the value of MK in wider clinical settings.
This study has several limitations. First, our simple size was relatively small, and similar
numbers of patients at each stage of fibrosis and inflammatory activity were not used,
therefore further studies with a larger and evenly distributed sample are needed to identify
cut-off values. Second, MR parameters derived from DKI and conventional DWI were
calculated by different imaging sequence, the ROI was placed as same as possible by vision.
Therefore, the matching error was inevitable.
In conclusion, MD can be reliable to do differentiation liver fibrosis at early stage and
inflammatory activity from normal liver and can serve as a valuable tool for predicting liver
fibrosis and inflammatory activity.

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Table 1
Demographic and pathological results
Characteristic Normal control Patients with P
subjects (n=20) Liver fibrosis (n=17) value
Age (year)a 41.44.9 (2746) 37.28.7 (2758) 0.066
Sex (M/F) 13/7 14/8 0.927
Body mass index (kg/m2)a 24.62.5 (20.628.0) 24.14.4 (16.131.2) 0.690
Fibrosis stage
No fibrosis, F0 20 0
Portal fibrosis, F1 10
Periportal fibrosis, F2 7
 Septal fibrosis, F3 3
Inflammatory activity
No activity, G0 20 0
Minimal inflammation, G1 6
Mild inflammation, G2 11
Moderate inflammation, G3 3
Note. Unless otherwise indicated, data are the number of patients, and data in parentheses are
percentages.
a
Data are the means standard deviation, and data in parentheses are the range.

Table 2
Comparison of diffusion parameters derived from DKI and conventional DWI in
differentiation liver fibrosis in different stages
F0 (n=20) F1 (n=10) F2 (n=7) F P
MD ( 10-3 mm2/s) 1.750.09ab 1.630.12 a 1.570.14b 11.323 <0.001*
MK 0.740.06 0.720.05 0.750.06 0.727 0.491
ADC ( 10-3 mm2/s) 1.280.08 1.220.19 1.170.13 1.881 0.168
Note. Data are the mean standard deviation. MD, mean apparent diffusion; MK, mean
kurtosis; ADC, apparent diffusion coefficient.
*
P < 0.05 indicates significant differences among normal and patients with different fibrosis
stages; aP = 0.002 indicates significant difference between F0 and F1 in MD; bP < 0.001
indicates significant difference between F0 and F2 in MD.

Table 3
Results of the quantitative analysis of the DWI and DKI in according to the inflammatory
activity
Grade 0 (n=20) Grade 1 (n=4) Grade 2 (n=13) Grade 3 (n=3)
MD ( 10-3 mm2/s) 1.760.12 1.620.12 1.610.11 1.400.06
MK 0.740.06 0.680.02 0.740.06 0.760.01
ADC ( 10-3 1.280.09 1.220.08 1.210.18 1.050.08
mm2/s)
Note. Data are the mean standard deviation. MD, mean apparent diffusion; MK, mean
kurtosis; ADC, apparent diffusion coefficient.
 A B C
Figure 1. Examples of placement of regions of interest (ROIs) on apparent diffusion
coefficient (ADC map, A), mean diffusion (MD map, B) and mean kurtosis (MK map, C).

Figure 2. Box plot of mean diffusion (MD) by diffusion kurtosis imaging and fibrosis stage.
MD of the liver decreased as the fibrosis stage increased, and have significant difference
between F0 vs. F1 (P = 0.002), F0 vs. F2 (P < 0.001).
Figure 3. Scatter plot of mean diffusion (MD) by diffusion kurtosis imaging correlated with
fibrosis stage.

Figure 4. Scatter plot of mean diffusion (MD) by diffusion kurtosis imaging correlated with
inflammatory activity.