To investigate the clinical usefulness of ultrasonography-based acoustic radiation force impulse (ARFI) elastography (ie, ARFI sonoelastography) in patients with a diagnosis of nonalcoholic fatty liver disease (NAFLD) and compare ARFI sonoelastography results with transient sonoelastography and serum fibrosis marker test results.
MATERIALS AND METHODS:
Written informed consent was obtained from all subjects, and the local ethics committee approved the study. Fifty-four patients with a liver biopsy-confirmed diagnosis of NAFLD (mean age, 50.6 years +/- 13.7) were examined. All patients with NAFLD and healthy volunteers underwent ARFI sonoelastography, transient sonoelastography, and serum liver fibrosis marker testing (hyaluronic acids, type IV collagen 7 S domain). Ten healthy volunteers underwent ARFI sonoelastography. ARFI sonoelastography results were compared with liver biopsy findings, the reference standard. ARFI sonoelastography findings were compared with liver biopsy, transient sonoelastography, and serum fibrosis marker test results. Student t testing was used for univariate comparisons; Kruskal-Wallis testing, for assessments involving more than two independent groups; and areas under the receiver operating characteristic curve (A(z)), to assess the sensitivity and specificity of ARFI sonoelastography for detection of stage 3 and stage 4 fibrosis.
Median velocities in the patients with NAFLD were 1.040 m/sec for those with stage 0 fibrosis, 1.120 m/sec for those with stage 1, 1.130 m/sec for those with stage 2, 1.780 m/sec for those with stage 3, and 2.180 m/sec for those with stage 4. The A(z) for the diagnosis of hepatic fibrosis stages 3 or higher was 0.973 (optimal cutoff value, 1.77 m/sec; sensitivity, 100%; specificity, 91%), while that for the diagnosis of stage 4 fibrosis was 0.976 (optimal cutoff value, 1.90 m/sec; sensitivity, 100%; specificity, 96%). Significant correlations between median velocity measured by using ARFI sonoelastography and the following parameters were observed: liver stiffness measured with transient sonoelastography (r = 0.75, P < .0001), serum level of hyaluronic acid(r = 0.459, P = .0009), and serum level of type IV collagen 7 S domain (r = 0.445, P = .0015).
There is a significant positive correlation between median velocity measured by using ARFI sonoelastography and severity of liver fibrosis in patients with NAFLD. The results of ARFI sonoelastography were similar to those of transient sonoelastography
Our study results demonstrate a significant positive correlation between median ARFI sonoelastographic velocity and liver fibrosis severity in patients with NAFLD. NAFLD is now a common cause of chronic liver disease. Its incidence in adults and children is rapidly increasing because of ongoing epidemics of obesity and type 2 diabetes (21,22). Patients with NAFLD can be divided into two categories: those with simple steatosis and those with NASH at liver biopsy. However, liver biopsy is an invasive and expensive procedure and is associated with a relatively high risk of complications (7). The biopsy procedure results in pain in 25% of all patients (23), and the risk of severe complications has been reported to be 3.1 cases per 1000 procedures (24). Moreover, the accuracy of biopsy for assessing the severity of liver fibrosis remains questionable, and intra- and interobserver variations have been observed (8,9,25–27). Furthermore, sampling errors are often reported, even in patients with NASH (28). Thus, a rapid and noninvasive method of detecting fibrosis in patients with NAFLD is of major clinical interest.
From an imaging viewpoint, we previously reported that transient sonoelastography can be used to measure fibrosis in patients with NAFLD (10,11). Recently, ARFI sonoelastography has been used to generate internal mechanical excitation noninvasively, and this method has attracted a great deal of attention for its use in the measurement of liver stiffness. Friedrich-Rust et al (29) compared ARFI imaging with both transient sonoelastography and serum fibrosis marker testing for the noninvasive assessment of liver fibrosis in patients with viral hepatitis. They reported that the results of US-based ARFI imaging for noninvasive measurement of liver fibrosis were comparable to those of transient sonoelastography and serum fibrosis marker testing.
To our knowledge, no investigators had previously evaluated the utility of ARFI sonoelastography for the assessment of liver fibrosis specifically in patients with NAFLD. Our results demonstrate that the median velocity measured by using ARFI sonoelastography increases as the fibrotic stage increases in these patients. The results also demonstrate a significant relationship between median ARFI sonoelastographic velocity and transient sonoelastographic liver stiffness measurement. Although we found a positive correlation between median ARFI sonoelastographic velocity and serum levels of liver fibrosis markers, the r values were relatively weak; thus, it is unlikely that this correlation can be used clinically.
The major advantages of transient sonoelastography and ARFI sonoelastography, as compared with liver biopsy, are that these techniques are painless, rapid, and have no associated complications and are, therefore, very easily accepted by patients. Moreover, ARFI sonoelastography can be integrated into a conventional
US system by using conventional US probes and therefore can be performed during
examinations of the liver, which are routinely performed in patients with
chronic liver disease. US
We found that the optimal median ARFI velocity for the diagnosis of NASH with severe fibrosis (stages 3 and 4) was 1.77 m/sec. Thus, in the future, patients with median velocities of more than 1.77 m/sec should be closely followed up, because it is likely that they have NASH with severe fibrosis. On the other hand, there is a possibility that the patients with a low median velocity might have simple steatosis. Therefore, in the future, patients with a low median velocity measured by using ARFI might be spared from undergoing liver biopsy.
We also found that the median velocity in patients with simple steatosis was lower than that in healthy volunteers. Possible reasons for this observation include the hypothesis that steatosis makes the liver softer because of fat deposition in the liver parenchyma. Unlike viral hepatitis, NASH has two aspects: steatosis and fibrosis. Therefore, in patients with NAFLD, it may be difficult to distinguish between simple steatosis and NASH with mild fibrosis with use of ARFI sonoelastography, although it can be performed more conveniently than transient sonoelastography.
One limitation of our study was that we calculated our accuracy measurements on the basis of the population being studied; therefore, our results are optimized for this specific population and likely include overestimations of performance. Another limitation was the relatively small number of patients, particularly those with higher grades of liver fibrosis. Because of this, we may not have adequately assessed the biologic variability in the patients with higher grades of fibrosis. Selection bias was another limitation because in this study, we did not examine patients who had any clinical evidence of hepatic decompensation. Furthermore, the liver biopsies were performed up to 12 months before ARFI sonoelastography and transient sonoelastography. There is the possibility that the degrees of steatosis and fibrosis had changed for the period. In this study, the same person performed the ARFI sonoelastographic and transient sonoelastographic examinations; this was an advantage because the two examinations could be performed with the patient in the same position. However, it cannot be denied that knowledge of other examinations could have biased results. At present, we have no choice but to depend on liver biopsy for the diagnosis of NASH.
In conclusion, to our knowledge, this is the first study conducted to investigate the potential clinical usefulness of a US-based ARFI elastography technique as a noninvasive method of assessing liver fibrosis in patients with NAFLD. Further investigation is required to ensure that ARFI sonoelastographic measurements are useful diagnostic markers of NASH.
Advances in Knowledge
There is a stepwise increase in the median velocity measured by using acoustic radiation force impulse (ARFI) sonoelastography with increasing histologic severity of hepatic fibrosis in fatty liver disease.
The median velocity in patients with simple steatosis is lower than that in healthy volunteers.
There is a relationship between median velocity measured by using ARFI sonoelastography and liver stiffness measured by using transient sonoelastography.
Implications for Patient Care
ARFI sonoelastography can be performed during standard
examinations of the liver, which
are routinely performed in patients with chronic liver disease. US
ARFI sonoelastography is a rapid and noninvasive method of detecting fibrosis in patients with nonalcoholic fatty liver disease.