Value of 3 Tesla diffusion-weighted magnetic resonance imaging for assessing liver fibrosis

Introduction

Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent cause of liver disease in Western countries. The development of non-alcoholic steatohepatitis (NASH) and fibrosis identifies a group with increased risk of liver-related deaths due to cirrhosis or hepatocellular carcinoma. The prevalence of NAFLD is estimated between 20% and 30% in Western countries [1,2], rising to 90% in the morbidly obese patients [3]. NASH, the more advanced and clinically important form of NAFLD, is less common, with an estimated prevalence of 2-3% in the general population [4], and 37% in the morbidly obese [3].

Liver biopsy is currently the gold standard to guide therapeutic decisions and assess prognosis in patients with NAFLD. The development of non-invasive methods for liver fibrosis evaluation aims to reduce biopsy-related risk and cost and to facilitate improved monitoring of disease progression. Serological assays, such as Fibrotest, and radiological methods like transient elastography (Fibroscan, Echosens, France) are used increasingly to evaluate liver fibrosis in NAFLD and other chronic liver diseases. Magnetic resonance imaging (MRI) is being evaluated as a non-invasive method of liver fibrosis assessment as well. Recently, MR elastography demonstrated excellent diagnostic accuracy with sensitivity and specificity of 98% and 99% respectively for detecting all grades of fibrosis [5].

Another MRI technique, diffusion-weighted imaging (DWI), has been lately used for liver fibrosis assessment. Diffusion is a physical property, which describes the microscopic random movement of (water) molecules driven by their internal thermal energy. Diffusion is quantitatively reflected in a diffusion coefficient, the apparent diffusion coefficient (ADC, expressed in mm2/s). Conflicting results regarding the reliability of DWI and apparent diffusion coefficient (ADC) values in liver fibrosis staging for patients with chronic liver disease are reported [6,7], while several studies have shown a decrease in hepatic ADC in liver cirrhosis [8-10].

The aim of our study was to assess the clinical performance of DWI performed with 3 Tesla MRI scanners for the assessment of liver fibrosis in patients with NAFLD.

Patients and methods

DWI

DWI was performed on a 3 Tesla MRI scanner (SIgna HDxT, General Electric, Milwaukee) with the aid of 8 channel Torso phased-array coil. Diffusion was in all cases acquired with respiratory gating with a Single Shot Echo Planar Imaging (DW-EPI) pulse sequence. Parallel imaging with Array Spatial Sensitivity Encoding Technique (ASSET) factor of 2 was used to improve image quality. DWI was performed in the axial plane with tri-directional diffusion gradients using three b values, namely, 0, 500, and 1000 s/mm2. The repetition time (TR) was on the average 10,288 ms (between 8,571 and 13,330), echo time (TE) between 63.7 – 67.9 ms, slice thickness 6 mm, gap between slices 1 mm, matrix 128 × 128, field of view 400 mm, number of excitations 4. The total acquisition time was on the average 4-5 min. The ADC maps were calculated by commercial workstation software (GE Healthcare) over four random locations within the liver using 1-2 cm2 regions of interest away from the intrahepatic vasculature. Mean ADC values were used for analysis (Fig. 1).

Figure 1

Diffusion-weighted image and apparent diffusion coefficient map obtained at b value of 0-1000 s/mm2 in a 63-year-old woman with non-alcoholic fatty liver disease and fibrosis stage 3

Results

Table 1 summarizes the baseline patients’ characteristics. 18 patients were included in our study. The median age of our patients was 52 years (range 23-73). The mean BMI was 28.1 kg/m2 (range 20.3-38.2). 78% percent of subjects were male. The median values for AST, ALT, glucose, cholesterol, triglyceride, albumin, total bilirubin, and alkaline phosphatase levels were 37.5 IU/L (18-132); 58 IU/L (19-132); 98 mg/dL (86-176); 217 mg/dL (169-275); 150 mg/dL (77-305); 4.5 g/dL (4.1-4.9); 0.7 mg/dL (0.1-1.4); 108 IU/L (57-330), respectively. The distribution of patients in different fibrosis stages was: 0 (n=1), 1 (n=7), 2 (n=1), 3 (n=5), 4 (n=4). Degree of steatosis was: 0 (n=0), 1(n=7), 2(n=3), 3(n=8).

Table 1

Patients’ characteristics

ADC correlation with histological parameters

Steatosis was not associated with ADC, neither for b value of 0-500 s/mm2 (P=0.64), or for b value of 0-1000 s/mm2 (P=0.09). Fibrosis stage was poorly associated with ADC at b value of 0-500 s/mm2 (r= -0.30, P=0.27) yet it was significantly associated with ADC at b value of 0-1000 s/mm2 (r= -0.57, P=0.01) For this b value (0-1000 s/mm2) the area under ROC curve was 0.93 for fibrosis stage ≥3 and the optimal ADC cut-off value was 1.16 × 10-3 mm2/s by maximizing the sum of sensitivity and specificity (positive predictive value: 100%, negative predictive value: 90%) (Fig. 2, 3). Namely, no patient with fibrosis stage <3 had ADC value lower than 1.16 × 10-3 mm2/s, whereas only 1 patient with fibrosis stage ≥3 had ADC value greater than 1.16 × 10-3 mm2/s. Significant decrease in ADC values was seen in patients with fibrosis stage ≥3 versus fibrosis stage ≤2, especially for b value of 0-1000 s/mm2 (Table 2).

Figure 2

Receiver operating characteristics curve for fibrosis stage ≥3 at b value of 0-500 s/mm2

Figure 3

Receiver operating characteristics curve for fibrosis stage ≥3 at b value of 0-1000 s/mm2

Table 2

Comparison of liver apparent diffusion coefficient (ADC) (value×10−3 mm2/s) for fibrosis stage ≤2 and ≥3 (n=18)

The ability to discriminate fibrosis stage ≥2 at b value of 0-1000 s/mm2 was also very good (area under ROC curve 0.88). As the sample of patients was very similar (only one patient had fibrosis stage 2) between the groups with fibrosis stage ≥3 and ≥2, the optimal ADC cut-off value for this group of patients was the same (1.16 × 10-3 mm2/s), but with different predictive values (positive predictive value: 100%, negative predictive value: 80%). However, the ability to diagnose cirrhosis (fibrosis stage 4) was poor (area under ROC curve 0.64, positive predictive value: 43%) and only exclusion of this condition could be safely predicted (negative predictive value: 91%).

Discussion

The diagnosis and treatment of patients with NAFLD depends significantly on liver fibrosis staging. Liver biopsy is still considered the ‘‘gold standard” for the assessment of liver fibrosis and is currently recommended by professional society practice guidelines. Although generally safe, this procedure is invasive and has a minor possibility of serious adverse events (hemorrhage, death) [12]. In addition, the accuracy of liver biopsy varies significantly depending on inter-observer variability and sampling error. This results in up to 30% false-negative results and underestimation of cirrhosis, especially in small (<1.5cm) or fragmented specimens [13-16].

During the last decade a number of non invasive methods for liver fibrosis assessment have been introduced. MRI methods like MR elastography, spectroscopy and DWI are being evaluated as non invasive methods of liver fibrosis assessment. Advantages of MRI methods include the ability to scan the whole liver to minimize sampling error, the lack of requirement for an acoustic window as in transient elastography, insensitivity in body habitus and ascites and, finally, the ability to obtain conventional MRI in the same setting.

DWI is affected by the biophysical properties of tissue cell organization (cell membranes, fibers and macromolecules), density, microstructure and microcirculation. Pathological processes which change the volume ratio or physical nature of intra- and extracellular spaces affect the diffusion of water molecules. Restricted or impeded diffusion is seen in tissues with high cellularity, e.g. tumors, abscesses, fibrosis and cytotoxic edema. Relative free or unimpeded diffusion is encountered in tissues with low cellularity or tissues with disrupted cell membranes, for example in cysts and necrotic tissues [17-20]. Low ADC values mean restricted diffusion, thus in tissues which are highly cellular. High ADC values are seen in areas with relative free diffusion, thus in tissues with low cellularity.

DWI performed with current generation scanners (1, 5 Tesla) does not appear to be reliable enough to replace liver biopsy [21]. Theoretically, the new generation 3 Tesla technology could improve hepatic ADC detection [22]. The increased signal to noise ratio inherent in the 3 Tesla scanners provides higher sensitivity in areas of restricted diffusion, while the use of parallel imaging through the reduction of TE reduces the susceptibility artifacts [23,24].

Our study showed a significant inverse correlation between liver fibrosis and ADC values taken in 3 Tesla DWI among NAFLD patients. This correlation was significantly associated with ADC at b value of 0-1000 s/mm2. ADC cut-off value of 1.16 × 10-3 mm2/s was shown to predict severe fibrosis (stage ≥3) thus providing a potentially useful tool for the assessment of these patients. To our knowledge there are only two reports regarding liver fibrosis correlation with ADC values performed on 3 Tesla MRI scanners in patients with chronic liver disease. The first one included 37 patients with chronic viral hepatitis and 34 healthy volunteers. The authors reported significant inverse correlation of ADC values with liver fibrosis with a b factor of 1000 s/mm2 [25]. The second one included 55 patients with chronic liver disease who had undergone DWI using 8 b-values at 3 Tesla. Significant correlation of ADC values with hepatic fibrosis was reported. Higher ADC values were seen in fibrosis stage F≤1 compared to fibrosis stage F=4 [26].

Conflicting results regarding liver fibrosis and DWI in 1.5 Tesla scanners are reported. Taouli et al [7] reported significant inverse correlation of ADC and liver fibrosis in patients with chronic liver disease with AUC of 0.896 and cut off value of 1.03 × 10-3 mm2/s at 0-1,000 b value for fibrosis stage ≥3. Koinuma et al [27] evaluated a large population of patients (n=163), 31 of whom underwent liver biopsy and found significant inverse correlation between hepatic ADC and fibrosis stage in lower b value (128 s/mm2). Sandrasegaran et al [21] reported significantly lower ADCs in cirrhotic livers compared with nonfibrotic livers but ADC values were not useful for differentiating patients with fibrosis stage ≥2 from those with a lower degree of fibrosis. Lewin et al [28] compared DWI in 54 hepatitis C patients and 20 healthy volunteers with FibroScan and FibroTest. They found that DWI was comparable to these tests in detecting severe fibrosis but they also reported significant overlap of ADC values between patients with mild and moderate fibrosis. Bakan et al [29] reported that lower ADC values were associated with higher fibrosis stages in 34 patients with chronic liver disease. Bonekamp et al [30] found that liver ADC values were inversely correlated with fibrosis stage. AUROCs of 0.79, 0.77, 0.77 and 0.79 were obtained for fibrosis stages 1,2,3, and 4 respectively.

This study also shows that ADC at b value at 0-1,000 s/mm2 has statistically significant inverse correlation with liver fibrosis compared to b value at 0-500 s/mm2. The sensitivity of a DWI sequence is characterized by its b value. The higher the b value, the more sensitive the sequence is to diffusion effects [21,31]. Boulanger et al [32] used DWI at b values of 50-250 s/mm2 in 18 chronic hepatitis C patients and 10 control subjects. They found no significant difference between the two groups. Interestingly the ADCs of patients with hepatitis C were even higher than those of controls. It is possible that differences between fibrotic and nonfibrotic liver cannot be detected at small b values (<300 s/mm2), which can increase the amount of perfusion contamination in ADC measurement [31,33]. In a recent study including 24 patients with chronic liver disease and 22 healthy volunteers, ADC values at b value of 750 s/mm2 or greater showed superior correlation with liver fibrosis compared to lower b values [34]. On the other hand, some researchers believe that there may be an advantage to calculating ADC values using an intermediate b value compared to a higher b value [35]. According to our results, we believe that 3 Tesla DWI at b value of 1,000 s/mm2 provides a relative advantage for liver fibrosis assessment compared to 1.5 Tesla technology scanners.

We acknowledge some limitations of our study. First, this is a pilot study where we report our preliminary experience with a small number of patients. Also, DWI is more expensive than other non invasive methods of liver fibrosis assessment with comparable effectiveness. In addition, MRE was shown to be superior in predicting liver fibrosis as compared with DWI in a recently published meta-analysis [36]. However, all studies included in this analysis were performed with 1.5 Tesla scanners. As it was recently pointed out, the strength of the magnetic field that the scanner uses plays a vital role in interpreting the results [37].

In conclusion, our findings suggest that 3 Tesla DWI can possibly predict the presence of advanced (≥3) fibrosis in patients with NAFLD especially when the b value is 0-1000 s/mm2. Future work is needed to assess a larger number of patients with NAFLD and to correlate 3 Tesla DWI findings with liver fibrosis. These new technology scanners may provide a useful tool for the treatment and follow up of this subset of patients.