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ARFI, FibroScan, ELF, and their combinations in the assessment of liver fibrosis: A prospective study
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Journal of Hepatology August 2012
Gonzalo Crespo1, Guillermo Fernandez-Varo2, Zoe Mari撲1, Gregori Casals2, Rosa Miquel3, Stella M. Mart地ez1, Rosa Gilabert4, Xavier Forns1, Wladimiro Jimenez2,5, Miquel Navasa1,
1Liver Unit, Hospital Cl地ic, CIBERehd, IDIBAPS, Barcelona, Spain; 2Department of Biochemistry and Molecular Genetics, Hospital Cl地ic, CIBERehd, IDIBAPS, Barcelona, Spain; 3Department of Pathology, Hospital Cl地ic, CIBERehd, IDIBAPS, Barcelona, Spain; 4Department of Radiology, Hospital Cl地ic, CIBERehd, IDIBAPS, Barcelona, Spain; 5Department of Physiology, University of Barcelona, CIBERehd, IDIBAPS, Barcelona, Spain
Background & Aims
Our aim was to evaluate a serologic marker (ELF) and two ultrasound-based methods (FibroScan® and ARFI), as well as their combinations, in the assessment of liver fibrosis.
Methods
One-hundred and forty-six patients (87 liver transplant recipients, 59 non-transplant patients) who underwent liver biopsy were prospectively included. We evaluated the diagnostic accuracy of FibroScan®, ARFI, ELF and the combination of ELF with either ARFI or FibroScan®. After analyzing in separate transplant and non-transplant patients, the whole cohort was divided into a training set and a validation set.
Results
ARFI imaging was successfully performed across the whole cohort, while FibroScan® failed in 16 (11%) patients. The three methods showed similar AUROCs and best cut-off values in transplant and non-transplant patients. In the training set, differences between the AUROCs of ARFI, FibroScan® and ELF to diagnose F2 (0.879, 0.861, and 0.764, respectively) and cirrhosis (0.936, 0.918, and 0.841) were not statistically significant, although both ultrasound-based methods showed higher accuracy than ELF. The combination of ELF with ARFI or FibroScan® increased the negative and positive predictive values of single tests for the diagnosis of F2 and cirrhosis. Similar results were obtained when the methods were tested in the validation set.
Conclusions
ARFI is as effective as either FibroScan® or ELF in the non-invasive assessment of liver fibrosis, and its inclusion in an ultrasound device could facilitate its incorporation into routine clinical practice. The combination of ARFI or FibroScan® with ELF may help better identify patients with or without significant fibrosis or cirrhosis.
Introduction
Evaluation of fibrosis is crucial in the assessment of chronic liver disease. Currently, histological assessment based on semi-quantitative scores is considered the best method for evaluating fibrosis, although biopsy has also some drawbacks that have led to the development of techniques geared towards a non-invasive assessment of liver fibrosis [1], [2].
Liver stiffness measurement (LSM) using transient elastography (TE, FibroScan®) is accurate in identifying significant fibrosis and especially cirrhosis in several liver diseases including liver transplant recipients [3], [4], [5], [6], [7]. Nevertheless, FibroScan® has some limitations, such as LSM failure in patients with narrow intercostal spaces or high body mass index [8] and increased stiffness values in patients with acute hepatitis [9] or extrahepatic cholestasis [10].
Another approach for evaluating liver fibrosis involves the use of serologic markers [2], [11], [12], [13], [14], [15]. Among them, the Original European Liver Fibrosis panel, that combines tissue inhibitor of matrix metalloproteinase type 1 (TIMP-1), hyaluronic acid (HA), aminoterminal propeptide of type III procollagen (PIIINP), and age, showed good diagnostic accuracy in detecting fibrosis in a large cohort of patients with chronic liver disease [16]. Subsequent studies have evaluated this panel, as well as its simplified modification, ELF (Enhanced Liver Fibrosis), in patients with different liver diseases [16], [17], [18]. Not less importantly, ELF has been shown to predict disease progression in several clinical settings [19], [20], [21].
Acoustic radiation force impulse (ARFI) is an ultrasound-based technology that uses short-duration, high intensity acoustic pulses to mechanically excite the tissue [22]. These radiation force excitations generate localized tissue displacements that result in shear waves, whose velocity (SWV) of propagation can be assessed in a region of interest (ROI) corresponding to a cylinder, 0.5cm long and 0.4cm wide, that can be targeted up to 5.5cm below the skin. Both the high-energy pulse and the conventional ultrasound pulse are generated by the same ultrasound probe, and results are expressed in m/s. Several studies have analysed the performance of ARFI [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], although some of these reports were heterogeneous, with small cohorts of patients and, in some cases, without the inclusion of liver biopsies. Moreover, no study has thus far attempted to combine ARFI with serologic markers in order to improve overall accuracy.
The aim of our study was to prospectively assess ARFI, FibroScan, and ELF and to explore their combined effectiveness in evaluating liver fibrosis, with biopsy serving as the reference standard.
Discussion
In the current prospective study, we have shown that the estimation of shear wave velocity with ARFI can provide a diagnosis of significant fibrosis and cirrhosis as accurate as FibroScan® or ELF, both in transplant recipients and immunocompetent patients with liver disease of varied aetiologies. Not less importantly, the combination of either ARFI or FibroScan® with ELF seems to increase the diagnostic accuracy of single tests, permitting to more confidently discard or confirm the presence of significant fibrosis or cirrhosis.
ARFI software is included in an ultrasound device. Ultrasound guidance is particularly helpful for ensuring that the ROI is placed in such a way that it avoids nearby vessels and ribs. This represents a significant advantage, especially when the region of interest measured by ARFI is smaller than it is for FibroScan®. Consistent with other reports [8], FibroScan® failed in 11% of patients. In contrast, we could measure shear wave velocity with ARFI in all of these same individuals. Most likely, ultrasound guidance helps facilitate the identification of a suitable place for elastographic measurements, thereby resulting in a higher number of patients with valid results. Moreover, ultrasound permits the evaluation of other features such as portal diameter, splenomegaly, and liver surface, which has recently been shown to be highly accurate in the diagnosis of early cirrhosis and seems to provide complementary information to that of liver stiffness [37]. Thus, the ability to perform ARFI and liver surface ultrasound examination during the same procedure offers a significant advantage and may facilitate the early diagnosis of cirrhosis.
Recent studies have suggested that the combination of serum markers with FibroScan® is highly accurate in the identification of liver fibrosis [38], [39]. In our population, the combined use of ELF with either FibroScan® or ARFI increased the PPV and NPV of single tests, still offering reliable identification of significant fibrosis and cirrhosis in a large proportion of patients. An important number of patients could thus have avoided liver biopsy, and had their disease staged with a high level of confidence. While this approach seems logical, as it uses ﾒcomplementaryﾓ methods, our results are based on a relatively low number of patients, thus larger, multicenter studies should be encouraged to confirm our findings.
It is important to acknowledge that the heterogeneous nature of the cohort is a significant limitation of our study, which included both transplant and non-transplant patients with liver disease of varied aetiologies. The combination of transplant and non-transplant patients in the same group may be particularly difficult to interpret, as fibrosis deposition and staging may be different in these groups of patients, and indeed a large number of transplant patients in our cohort did not have significant fibrosis. To try to solve in part this drawback, we first studied separately transplant and non-transplant patients, being able to show similar results in terms of diagnostic accuracy and best cut-off values in the two groups. This allowed us to analyze the entire cohort splitting the whole population into a training set and a validation set, which were comparable in terms of transplant patients proportion and prevalence of significant fibrosis and cirrhosis. Regarding the different aetiologies of the liver diseases, although our findings would anyway require further confirmation in single-etiology studies, it should be kept in mind that daily clinical work includes patients with liver disease of different aetiologies, and perhaps the results of the current study are more representative of what is typically seen in routine clinical practice.
In summary, ARFI, FibroScan® and ELF are reliable methods for assessing fibrosis in patients with varying forms of liver disease, including liver transplant recipients. Indeed, the combined use of ELF with either ARFI or FibroScan® seems a promising approach that may increase the diagnostic accuracy of these tests. The incorporation of ARFI in conventional ultrasound devices may facilitate the introduction of elastography into surveillance programs.
Results
Patient characteristics
Twenty-nine patients met exclusion criteria, including 20 biopsies shorter than 15mm or with less than six portal tracts, so the final cohort comprised 146 patients (87 transplant and 59 non-transplant patients). Patientsﾕ characteristics are summarized in Table 1.
Applicability and correlation of ARFI and FibroScan® in non-transplant and transplant patients
ARFI imaging was successfully performed in all patients, whereas FibroScan® failed in 16 cases (11%), 8 transplants (9%) and 8 non-transplants (14%). FibroScan® failure was significantly associated with higher BMI and longer abdominal perimeter in the two groups (p<0.02).
ARFI significantly correlated with FibroScan® in non-transplant patients (r=0.826, p<0.001, Fig. 1A), as well as in transplant recipients (r=0.887, p<0.001, Fig. 1B).
Relationship between fibrosis staging and non-invasive methods in non-transplant and transplant patients
In non-transplant patients, we found a significant association between fibrosis stages and ARFI, FibroScan®, and ELF (Kruskal-Wallis p<0.001 for all comparisons). Median values of ARFI according to fibrosis stages were 1.17 (F0), 1.4 (F1), 1.46 (F2), 1.77 (F3), and 2.6m/s (F4), while median FibroScan® measurements were 4.8, 7.5, 8.4, 13.3, and 22.3kPa, respectively, and median values of ELF panel were 8.7, 8.9, 9.4, 10.6, and 11.
In transplant patients, the relationships between the different non-invasive methods and fibrosis staging were also statistically significant (p<0.001 for all methods). Median ARFI measurements according to fibrosis stages were 1.16, 1.29, 1.51, 2.21, and 2.25m/s; median FibroScan® measurements were 5.2, 7.9, 10, 17.6, and 22.9kPa; and median ELF values were 8.85, 9.2, 10.5, 11.5, and 13.
In the 10 healthy volunteers, median values for ARFI and FibroScan® were 1.06m/s and 4.4kPa, respectively.
Diagnosis of F2 and cirrhosis in non-transplant and transplant patients
In non-transplant patients, differences between the AUROCs of the three methods for the diagnosis of F2 were not significantly different (Fig. 2A), while ARFI was significantly better than ELF to diagnose cirrhosis (p=0.05) (Fig. 2B). The diagnostic performance of the three methods is detailed in Table 2.
Fig. 2C and D depict the AUROCs of ARFI, FibroScan®, and ELF for the diagnosis of F2 and cirrhosis in transplant recipients. Again, while the three methods were comparable to diagnose F2, ARFI performed significantly better than ELF for cirrhosis (p=0.05). The diagnostic performance of ARFI, FibroScan®, and ELF in transplant patients is shown in Table 2.
Combination of complementary methods in non-transplant and transplant patients
We then aimed at combining the serum marker, ELF, with either ARFI or FibroScan® using the thresholds shown in Table 2. In non-transplant patients, the combination of ARFI and ELF yielded a PPV of 78% and NPV of 85% for the diagnosis of F2, avoiding 88% biopsies, and correctly classifying 71% of patients. The combination of FibroScan® and ELF showed a PPV of 85% and NPV of 90%, correctly classifying 59% of patients, and avoiding 68% biopsies. For the diagnosis of cirrhosis, the combination of ELF with ARFI or FibroScan® showed PPV of 93% and 70%, respectively, and NPV of 97% and 97%, respectively. The proportion of correctly classified patients and avoided biopsies was 81% and 85% for the combination of ARFI and ELF and 68% and 74% for the combination of FibroScan® and ELF.
In transplant patients, PPV and NPV of the combination of ARFI and ELF for F2 were 86% and 88%, avoiding 71% biopsies, and correctly classifying 62% of patients. PPV and NPV of the combination of FibroScan® and ELF were 79% and 87%, avoiding 66% biopsies, and correctly classifying 55% of patients. For the diagnosis of cirrhosis, ARFI and ELF showed PPV and NPV of 50% and 99%, while figures for the combination of FibroScan® and ELF were 46% and 99%, respectively. The proportion of correctly classified patients and avoided biopsies was 71% and 80% for the combination of ARFI and ELF and 62% and 71% for the combination of FibroScan® and ELF.
Diagnosis of F2 and cirrhosis and combinations of methods in the whole cohort: training and validation sets
As shown in Table 2 and Fig. 2, the three methods exhibited similar cut-off values and high diagnostic accuracy in transplant and non-transplant patients. For this reason, we aimed at simplifying the approach by analysing the entire population with single cut-off values. To this end, the whole cohort was divided into a training set (patients included in 2009-2010, n=88, 60% of the total population), in which cut-off values were developed, and a validation set (patients included in 2011, n=58, 40%). Table 3 shows the baseline characteristics of the two groups. Fig. 3A and B depict the AUROCs of the three methods in the training cohort for the diagnosis of F2 and cirrhosis, respectively; and their diagnostic performance is shown in Table 4. We did not find significant differences between the AUROCs of the three methods for the diagnosis of F2 or cirrhosis.
The combination of ELF and ARFI had a PPV and NPV of 60% and 98% for the presence of cirrhosis, while figures for the combination of FibroScan® and ELF were 54% and 100%, respectively.
AUROCs for the diagnosis of F2 and cirrhosis in the validation set are shown in Supplementary Fig. 1. The three methods were comparable to diagnose F2, while ARFI and FibroScan® were significantly better than ELF to diagnose cirrhosis. In the validation set, for the diagnosis of F2, the combination of ARFI and ELF using the cut-offs developed in the training set had a PPV and NPV of 88% and 95%, respectively, correctly identifying 40/58 patients (69%) and avoiding 44/58 (76%) biopsies. Similarly, the combination of FibroScan® and ELF had a PPV and NPV of 79% and 100%, respectively, correctly classifying 34/58 (59%) patients and avoiding 39/59 (67%) biopsies. For the diagnosis of cirrhosis, PPV and NPV of ARFI plus ELF were 73% and 100%, and figures for the combination of FibroScan® and ELF were 64% and 100%, respectively.
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