Abstract
Background
Nonalcoholic fatty liver disease (NAFLD) is becoming the most common cause of cirrhosis. Although magnetic resonance spectroscopy (MRS) is considered the gold standard, it has a few limitations. The role of diffusion-weighted imaging (DWI), which is a simpler sequence, in the diagnosis and grading of fatty liver is not well studied. The aim of the study was to investigate the value of DWI in the diagnosis and grading of hepatic steatosis in patients with NAFLD.
Materials and methods
Fifty-one adults (mean age: 38 years; 28 men, 23 women) with NAFLD, diagnosed clinically and by ultrasonography (USG), were included in the study after obtaining informed consent and approval from the institute ethics committee. USG was performed for grading of hepatic steatosis in all patients, followed by magnetic resonance imaging with DWI and MRS, on a 1.5T scanner. The mean apparent diffusion coefficient (ADC) values and proton density fat fraction (PDFF) were calculated, and MRS was used as the gold standard. The mean ADC values were compared with the PDFF and USG grades.
Results
There was a weak correlation between ADC values and PDFF (r = −0.36; P < 0.05). In addition, there was a weak correlation between the ADC values of the liver and USG grade (r = −0.34; P < 0.05). However, an overall increase in USG grades and PDFF was associated with decrease in the mean ADC value (P < 0.001).
Conclusion
DWI is not accurate in the diagnosis and grading of hepatic steatosis in patients with NAFLD. However, a significant increase in fat deposition in the liver lowers the ADC values.
Keywords: nonalcoholic fatty liver disease, diffusion-weighted imaging, magnetic resonance imaging, MR spectroscopy, fatty liver
Abbreviations: ADC, Apparent Diffusion Coefficient; DWI, Diffusion-Weighted Imaging; HCC, Hepatocellular Carcinoma; MRI, Magnetic Resonance Imaging; MRS, Magnetic Resonance Spectroscopy; NAFLD, Nonalcoholic Fatty Liver Disease; NASH, Nonalcoholic Steatohepatitis; PDFF, Proton Density Fat Fraction; USG, Ultrasonography
Nonalcoholic fatty liver disease (NAFLD) is a disease spectrum including simple hepatic steatosis, steatohepatitis, and hepatic fibrosis.1 Chronic fibrosis in these patients may lead to end-stage liver disease and increase the risk for development of hepatocellular carcinomas.2,3 Ultrasonography (USG) is the universal initial imaging modality in the detection and grading of fatty liver in patients with NAFLD. But various studies have shown that the accuracy of USG is limited with sensitivity and specificity ranging from 60 to 95%, and this is particularly low in mild steatosis.4 Currently, the imaging gold standard for the quantification of hepatic steatosis is magnetic resonance spectroscopy (MRS), which is replacing the invasive liver biopsy in many centers.5,6 Although MRS is accurate in quantifying hepatic fat content, it has a few limitations.7 MRS requires additional processing software which adds to the cost and limits its wide use. Furthermore, the results of MRS may be influenced by low signal-to-noise ratio, respiratory motion causing phase and frequency shift artifacts, partial volume averaging, and large water and lipid peaks masking other metabolite peaks.7 Hence, there is a need for a simpler but more accurate imaging technique to grade hepatic steatosis.
Diffusion-weighted imaging (DWI) is a novel functional magnetic resonance imaging (MRI) technique which measures the motion of water molecules in the extracellular space of tissues and is represented by apparent diffusion coefficient (ADC) values.8,9 Its role in the evaluation of liver pathologies has been studied and validated extensively, especially in the detection and characterization of focal liver lesions.10, 11, 12, 13 In the last decade, DWI has shown potential benefits in diffuse diseases of the liver, especially in the diagnosis and monitoring of fibrosis in cases of cirrhosis.14,15 Few sporadic studies have shown that diffuse hepatic steatosis affects the ADC values of the liver.16,17 However, the role of DWI in diagnosis or quantification of hepatic steatosis and its relationship with various grades of hepatic steatosis is not clearly established.
With this background, we aimed to assess the value of DWI in the diagnosis and grading of hepatic steatosis in cases of NAFLD and compare it with USG and MRS.
Materials and methods
This study was approved by the institute ethics committee (reference number – IESC/T-472/29.11.2013 by institute ethics committee/ethics subcommittee), and written informed consent was obtained from the study population. Consecutive adult subjects (>18 years of age) with clinical and USG diagnosis of NAFLD were included in this study. Subjects with history of diabetes, thyroid disease, seropositivity for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus, persistent elevation of serum transaminases for more than three months, alcohol intake of more than 20g per day, and chronic drug intake such as corticosteroids were excluded. The body weight and body mass index were measured, and the liver function tests and lipid profile tests were carried out in all patients. USG and MRI with DWI and MRS were performed in all the cases within a span of one week.
USG for assessing the grade of fatty liver was performed on Aixplorer USG machine (SuperSonic Imagine, Aix-en-Provence, France) using the curvilinear transducer, after an overnight fast. The fatty liver was graded (grades I to III) on the greyscale USG, as per following standard definitions: grade I – increased liver echogenicity, more than that of the renal cortex with preserved echogenic walls of the portal vein branches; grade II – increased liver echogenicity with nonvisualization of the echogenic walls of the portal vein branches but with appreciable outline of the diaphragm; grade III – increased liver echogenicity with shadowing and nonvisualization of diaphragmatic outline.
MRI was performed on a 1.5 T scanner (Achieva, Philips, Best, Netherlands) using a phased array torso coil. In addition to the standard T1- and T2-weighted gradient echo sequences, DWI and MRS were performed in all cases. The following were the parameters:
-
1.
DWI, using single-shot spin-echo echo-planar technique with fat suppression, was performed in axial plane, during free breathing, using b values 0, 400, and 800; repetition time (TR) – 4184 ms; echo time (TE) – 64 ms; slice thickness – 5 mm; number of averages – 6; and time of acquisition – 3 min. The ADC maps were automatically generated by the scanner. The higher b-value of 800 s/mm2 was used as recommended by studies to minimize the effects of perfusion.18,19
-
2.
MRS was performed in free breathing, with voxel placed in 3 different areas on the right lobe of the liver avoiding major vessels, using point-resolved spectroscopy technique. The parameters were as follows: voxel size – 30 × 30 × 30 mm, TE – 34 ms, TR – 2000 ms, flip angle – 90°, number of averages – 40, phase cycles – 8, time – 1 min 24 s.
The images were evaluated by two radiologists with five and fourteen years of experience (N.M. and K.S.M.), in consensus. The water and fat signals obtained with MRS were postprocessed using iterative shimming till the baseline was relatively horizontal on the workstation. The proton density fat fraction (PDFF) was calculated using the following formula: PDFF = Afat/(Awater + Afat), where Afat is the area under the spectral peak at 1.3 ppm (fat peak) and Awater is the area under the peak at 4.8 ppm (water peak) (Figure 1).20,21 This was calculated for each of the three voxels in the right lobe of the liver, and the mean was recorded. For the sake of convenience, we categorized the subjects into four groups based on the PDFF as shown in Table 1.
Figure 1.
A 39-year-old woman with grade II fatty liver on ultrasonography. (A) MR spectroscopy shows lipid peak at 1.3 ppm (short arrow) and water peak at 4.6 ppm (long arrow) with area under curve (AUC) for water being 574.9 and lipid being 157.4, and the calculated fat fraction was 21.4%. (B and C) Axial diffusion weighted (B) and apparent diffusion coefficient (C) images show an ADC value of 0.94 × 10−3 mm2/s. ADC, apparent diffusion coefficient; MR, magnetic resonance.
Table 1.
Magnetic Resonance Spectroscopy–Based Grading of Fatty Liver.
| MR grade | Mean PDFF (%) |
|---|---|
| 0 | 0–5 |
| 1 | 5–15 |
| 2 | 15–25 |
| 3 | >25 |
MR, magnetic resonance; PDFF, proton density fat fraction.
Subsequently, three regions of interest (ROIs), each with minimum size of 1 cm2, were drawn on the right lobe of the liver on the diffusion-weighted images (b800), the ROIs corresponding approximately with the MRS voxel location. These ROIs were then copied and pasted on the ADC maps to obtain the ADC values (Figure 1). Then, the mean of the three ADC values was calculated.
Statistical analysis was performed using SPSS, version 21.0, software (SPSS, IBM, Chicago). Descriptive statistics was used to define patient characteristics. The hepatic fat content provided by PDFF obtained on MRS was considered as the gold standard. The ADC values were compared with PDFF values and USG grades of fatty liver, and Pearson's correlation coefficient (r) was calculated. A p-value of <0.05 was considered significant.
Results
Eighty-five nonalcoholics and nondiabetics with clinical suspicion of NAFLD were referred for screening for fatty liver on USG. Of these, 26 patients did not have fatty liver and were excluded. Three cases were newly diagnosed with diabetes mellitus and were excluded. Five patients were excluded due to technical errors in MRS fat quantification (which occurred in the initial part of the study). Finally, a total of 51 patients (28 men, 23 women; mean age: 38 years; age range: 20–53 years) were included in the study (Figure 2).
Figure 2.
Flow chart of patient selection in the study group. DWI, diffusion-weighted imaging; MR, magnetic resonance; MRS, magnetic resonance spectroscopy; USG, ultrasonography.
The demographic characteristics of all the subjects, based on MRS grades and USG grades of fatty liver, are tabulated in Table 2 and Table 3, respectively. The mean values of liver function tests and lipid profile tests were normal in the different groups of fatty liver, indicating that these are affected variably and very late in the course of the disease.
Table 2.
Demographic Characteristics of the Study Population on the Basis of MRS Grades of Fatty Liver. DL
| MRS grade | Normal values | 0 | 1 | 2 | 3 |
|---|---|---|---|---|---|
| Number of cases (n) | – | 4 | 21 | 18 | 8 |
| Mean BMI (kg/m2) | Below 25 | 25.10 (23.7–26.7) | 27.88 (24.6–29.7) | 29.30 (26.7–34.2) | 28.72 (27.1–35.3) |
| Mean AST (IU) | 0–40 | 24 (16–46) | 24 (18–55) | 25 (18–113) | 27 (21–126) |
| Mean ALT (IU) | 0–40 | 18 (16–41) | 22 (17–49) | 24 (17–88) | 26 (16–105) |
| Mean serum cholesterol (mg/dl) | Less than 200 | 187.0 (130.4–218) | 193.3 (154–240) | 197.7 (155–260) | 187.1 (158–214) |
| Mean serum LDL (mg/dl) | Less than 130 | 114.0 (72–141) | 101.0 (65.2–117.8) | 108.8 (31.2–133) | 109.8 (50.4–160) |
| Mean serum HDL (mg/dl) | More than 40 | 42.0 (26.8–53) | 45.3 (35–54) | 47.0 (34–69) | 42.3 (19.5–56) |
| Mean serum triglycerides (mg/dl) | Less than 150 | 156.0 (74–220) | 234.6 (131–414) | 212.2 (146–390) | 175.3 (134–296) |
| Mean ADC ×10−3 mm2/s (range) | – | 1.13 (0.99–1.27) | 1.11 (0.95–1.50) | 1.05 (0.83–1.47) | 1.01 (0.82–1.36) |
Values in the brackets indicate range. ADC, apparent diffusion coefficient; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MRS, magnetic resonance spectroscopy.
Table 3.
Demographic Characteristics of the Study Population on the Basis of USG Grades of Fatty Liver.
| USG grade | Normal values | I | II | III |
|---|---|---|---|---|
| Number of cases (n) | – | 21 | 17 | 13 |
| Mean BMI (kg/m2) | Below 25 | 27.25 (23.7–31.2) | 28.65 (27.2–33.4) | 29.34 (28–35.3) |
| Mean AST (IU) | 0–40 | 24 (16–48) | 25 (16–55) | 29 (22–126) |
| Mean ALT (IU) | 0–40 | 21 (16–41) | 19 (13–49) | 27 (17–105) |
| Mean serum cholesterol (mg/dl) | Less than 200 | 200.0 (130.4–220) | 200.1 (164–250) | 182.0 (151–214) |
| Mean serum LDL (mg/dl) | Less than 130 | 110.0 (72–128) | 101.8 (79–149) | 105.2 (71–160) |
| Mean serum HDL (mg/dl) | More than 40 | 44.0 (26.8–54) | 48.4 (35–69) | 42.5 (19.5–56) |
| Mean serum triglycerides (mg/dl) | Less than 150 | 205.5 (74–286) | 249.2 (146–414) | 175.5 (134–296) |
| Mean ADC ×10−3 mm2/s (range) | – | 1.12 (0.95–1.50) | 1.08 (0.95–1.47) | 0.99 (0.82–1.36) |
| Mean PDFF (%) (range) | – | 9.65 (1.50–15.10) | 17.93 (11.0–24.15) | 29.62 (21.6–41.45) |
Values in the brackets indicate range. ADC, apparent diffusion coefficient; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PDFF, proton density fat fraction; USG, ultrasonography.
Comparison of ADC with PDFF
There was a weak inverse but statistically significant correlation between the mean ADC values and the grades of fatty liver on MRS (r = −0.36; P = 0.008), as shown in Figure 3. The mean ADC values showed a gradual decrease with an increase in PDFF, suggesting restriction of diffusion with increase in hepatic fat fraction (Figure 4). On statistical analysis, the difference in ADC values was not significant between grade 0 and grade 1 (P = 0.21) and between grade 2 and 3 (P = 0.54). However, there was statistically significant (P < 0.001) difference in mean ADC values between grade 1 and 2, grade 0 and 2, grade 0 and 3, and grade 1 and 3. Four patients had elevated transaminases. The mean ADC values in these patients were 0.95 x 10−3mm2/s, 1.06 x 10−3 mm2/s, 1.10 x 10−3 mm2/s, and 1.19 x 10−3 mm2/s, respectively. The transaminase levels returned to normal in three months, and the clinical diagnosis was NAFLD.
Figure 3.
Box plots comparing the mean ADC values of the liver with MRS grades (A) and USG grades (B) of fatty liver. ADC, apparent diffusion coefficient; MRS, magnetic resonance spectroscopy; USG, ultrasonography.
Figure 4.
Scatter diagram comparing the ADC values of the liver and the mean PDFF. ADC, apparent diffusion coefficient; PDFF, proton density fat fraction.
Comparison of ADC with USG
There was a weak inverse correlation between the mean ADC values and grade of fatty liver on USG which was statistically significant (r = −0.34; P = 0.013), as shown in Figure 3. The ADC values showed a gradual decrease with increase in grade of fatty liver. On statistical analysis, there was no significant difference of mean ADC values between grade 1 and grade 2 (P = 0.35) and between grade 2 and grade 3 (P = 0.08). However, between grade 1 and grade 3, there was statistically significant difference in mean ADC values (P = 0.01).
Discussion
In the present study, there was a weak but significant inverse correlation between mean ADC values and PDFF of the liver (r = −0.36; P < 0.05), suggesting that ADC values are not accurate in quantifying hepatic fat content. However, when ADC values of alternate grades were compared (i.e, grade 0 vs 2 and grade 1 vs 3), the difference was significant. Similarly, the ADC values showed significant difference between grade 1 and grade 3 fatty liver on USG. These findings suggest that ADC values decrease with increasing fat deposition in the liver, but it may not be sensitive to small changes in fat content.
It has been suggested that fat deposition within and between hepatocytes decreases interstitial space and reduces molecular diffusion.16 Poyraz et al16 retrospectively compared the ADC values of fatty liver (n = 42) and control (n = 78) groups and found a weak inverse relationship with the hepatic fat fraction (r = −0.39; P value < 0.001), similar to that of the present study. The ADC values ranged from 1.30 ± 0.21 x 10−3 mm2/s in mild fatty liver (fat fraction of 5–10%) to 1.09 ± 0.21 x 10−3mm2/s in severe fatty liver (fat fraction of 20–35%). However, the method used for calculation of hepatic fat fraction was dual-echo T1-weighted gradient echo sequence, the results of which are affected by concomitant deposition of iron.22 Furthermore, the b-values used by them for DWI were 0 and 1000 mm2/s, which may have led to higher ADC values than the present study. Besheer et al23 evaluated the effect of steatosis on ADC values in 268 patients (208 – nonsteatotic; 60 – steatotic) of chronic hepatitis C genotype 4 with early (METAVIR stages F1 and F2) and advanced (METAVIR stages F3 and F4) fibrosis groups. They found that the ADC values were significantly (P < 0.001) lower in the patients with steatosis than in the ones without steatosis (1.52 ± 0.17 × 10−3 mm2/s versus 1.65 ± 0.11 × 10−3 mm2/s in early fibrosis and 1.07 ± 0.16 × 10−3 mm2/s versus 1.35 ± 0.11 × 10−3 mm2/s in advanced fibrosis groups, respectively). However, liver fibrosis was a confounding factor in their study as it also independently affects the ADC values. In a study by Dijkstra et al,24 it was found that hepatic fat significantly decreases molecular diffusion in the liver (r = −0.446, P-value <0.001), even in patients with nonsteatotic hepatic fat deposition (i.e, < 5.5%). On the contrary, a study by d'Assignies et al17 showed that DWI did not help in differentiating patients with steatosis (n = 20) from healthy controls (n = 24), as the ADC values were 1.96 ± 0.38 (x 10−3 mm2/s) and 1.93 ± 0.28 (x 10−3 mm2/s), respectively. This could be due to the lower b-values (50, 100, 200, 300, 400) in the study.
The study also compared ADC with USG grades of hepatic steatosis, which showed weak inverse correlation. There are no other studies in the literature which have compared ADC values with USG grades of fatty liver.
Steatosis reduces free movement of water molecules and thus causes restriction of diffusion on DWI. Although there was a significant inverse relation between liver fat content and ADC, the correlation coefficient was low (r = −0.36). One reason could be the fact that the fat suppression technique used in the DWI sequence may incompletely and heterogeneously saturate fat and this may influence the ADC values.25 The ADC values are less sensitive to the alteration of diffusion properties in NAFLD than other quantitative parameters such as diffusivity and perfusion fraction.25 Furthermore, NAFLD is a dynamic disease with heterogeneous deposition of fat, and in addition to fat, there is inflammation (steatohepatitis) and fibrosis in the liver parenchyma as the disease progresses.26 In a study by Leitão et al,27 evaluating the effects of steatosis, inflammation, and fibrosis on the diffusion parameters in chronic liver disease (n = 68), a multiple regression model showed that steatosis more significantly reduced the ADC than fibrosis. Inflammation did not significantly affect the diffusion parameters. In the present study, only four patients had alterations in the liver function tests which returned to normal in three months, and hence, the possibility of inflammation was low. Another reason could be the fact that ADC in patients with NAFLD may be affected by concomitant iron deposition due to T2∗ effects.21 However, iron deposition in NAFLD is seen in only one third of patients and mostly in the stage of steatohepatitis and along with fibrosis.28 Severe steatosis (>25% fat) was seen in only eight patients in the present study. Hence, the effect of iron on ADC was possibly minor.
There were a few limitations in the study. The sample size was small. There was no histological confirmation of fatty liver in the study population, and MRS was considered as the gold standard. Absence of biopsy may have resulted in missing cases of nonalcoholic steatohepatitis, which may have affected the results. However, none of the cases had clinical indication for performing a biopsy, and hence, it was not performed. Furthermore, liver stiffness also was not evaluated as it is known that it is affected both by fibrosis and fatty infiltration. The ROIs drawn on the DWI may not have been representative. Although matching was made with ROIs of MRS, some mismatch was inevitable. Although cases of cirrhosis or hemochromatosis were excluded, tests to detect fibrosis and iron deposition in the liver, which could affect ADC values, were not performed.
In conclusion, DWI had no significant role in the quantification or grading of hepatic steatosis in the current short series. However, the ADC values decreased with increase in hepatic fat content with low but significant correlation. More studies in a larger cohort of patients with biopsy correlation are necessary to clearly establish the role of DWI in the grading of hepatic fat in patients with NAFLD.
CRediT authorship contribution statement
Nikhil Makhija: Methodology, Investigation, Data curation, Writing – original draft. Naval K. Vikram: Investigation, Writing-Reviewing and Editing. Deep N. Srivastava: Supervision, Writing-Reviewing and Editing. Kumble S. Madhusudhan: Conceptualization, Writing-Reviewing and Editing, Supervision.
Conflicts of interest
The authors have no conflicts of interest to declare.
Funding
None.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jceh.2021.02.008.
Appendix A. Supplementary data
The following is/are the Supplementary data to this article:
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