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MRI-PDFF, MRE, Fibroscan for Fibrosis, Fatty Liver
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Newer quantitative ultrasound-based techniques have emerged and have been shown to be highly correlated with MRI-PDFF assessments (Spearman ρ = 0.80; P < .0001),80 and the most studied of these techniques is the controlled attenuation parameter (CAP) based assessments. By concomitantly assessing hepatic steatosis and liver stiffness through transient elastography, CAP based ultrasound assessments have been shown to provide a more accurate assessment of hepatic steatosis across a wide range of patient populations.80-87 Recently, a direct comparison between MRI-PDFF and CAP for quantify hepatic steatosis was performed, and MRI-PDFF was demonstrated to be more accurate for the detection of grade 1 steatosis (MRI-PDFF: AUC 0.98, 95% CI 0.96 - 1.00 vs. CAP: AUC 0.88, 95% CI 0.80 - 0.95), for differentiating between grade 1 and 2 steatosis (MRI-PDFF: AUC 0.90, 95% CI: 0.81 - 0.98 vs. CAP: AUC 0.73, 95% CI: 0.64 - 0.81), and for differentiating between grade 2 and 3 steatosis (MRI-PDFF: AUC 0.79, 95% CI: 0.64 - 0.95 vs. CAP: AUC 0.70, 95% CI: 0.58 - 0.83).88 Thus, although ultrasound may be an inexpensive diagnostic tool for use in clinical practice with modest diagnostic accuracy, MRI-PDFF remains the most accurate diagnostic tool available for quantifying hepatic steatosis and the enhanced accuracy associated with this imaging modality will help to overcome its expense by avoiding the excess costs associated with complications from false positive or false negative results. If MRI-PDFF is not readily available for routine clinical use, then its greatest value in clinical practice will come in those individuals identified to be at risk for progression to NASH or NASH related complications, and a therapeutic intervention is planned. A baseline and follow-up assessment 6 months later, at a referral center with expertise in MRI-PDFF, will help to ensure the most accurate quantification of disease severity and response to therapy which has implications on the long-term disease related morbidity and mortality.
Importance of fibrosis when quantifying hepatic steatosis: the need for a composite biomarker
It is important to note that, although MRI-PDFF is a highly accurate, reliable, and responsive diagnostic tool for quantifying hepatic steatosis in NAFLD, its application as a biomarker in patients with more advanced liver disease is limited by the severity of fibrosis present. 29, 56 Permutt et al.29 demonstrated that average MRI-determined PDFF and histology-determined steatosis grade remained relatively stable at fibrosis stage 0-3, but dropped significantly at stage 4. Schwimmer et al.89 similarly demonstrated that the correlation between MRI-PDFF and histology was significantly (P < 0.01) weaker in children with stage 2-4 fibrosis (0.61) than children with no fibrosis (0.76) or stage 1 fibrosis (0.78). Thus, if MRI-PDFF is to be used for assessing response to therapy in patients with more aggressive and advanced disease courses, a concomitant biomarker based-assessment of fibrosis will be needed. It is likely that MRE-based stiffness measurements may address this need, as discussed below.
MRE based assessment of hepatic fibrosis
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MRI and MRE for non-invasive quantitative assessment of hepatic steatosis and fibrosis in NAFLD and NASH: Clinical trials to clinical practice:
Together these studies demonstrate that MRI-PDFF is highly responsive to changes in hepatic steatosis, this change in MRI-PDFF assessments over time correlates to a true biologic response (change in liver enzymes) and meaningful clinical outcome (change in body weight), and co-localization of ROIs is needed to ensure a high degree of accuracy for quantifying change over time. Additionally, since MRI-PDFF is more sensitive to longitudinal change in steatosis than biopsy with histology scoring, it is more likely to detect both positive and adverse therapeutic responses, providing further support for its use as a surrogate biomarker of hepatic steatosis.
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[ Magnetic Resonance Elastography of Liver: Technique, Analysis and Clinical Applications - Studies have also shown that MRE can be used to detect liver fibrosis well before other imaging signs of fibrosis are seen (Fig 9).A number of MRI-based techniques have been evaluated for assessing hepatic fibrosis, including diffusion weighted imaging (DWI), perfusion MRI, MR spectroscopy (MRS), and MR Elastography (MRE) (19-22). Studies comparing the MRE with Fibroscan are few (27, 47). In one study, MRE had a higher technical success rate than Fibroscan and a better diagnostic accuracy (0.994 for F > 2; 0.985 for F > 3; 0.998 for F > 4) than Fibroscan and aspartate aminotransferase to platelets ratio index (APRI), and the combination of Fibroscan and APRI (0.837, 0.709, and 0.849 for F > 2; 0.906, 0.816, and 0.936 for F > 3; 0.930, 0.820, and 0.944 for F > 4, respectively) (27).
MRE is an MRI-based method for quantitatively imaging the direct consequence of liver fibrosis - increased stiffness of the hepatic parenchyma (23-28). The technique provides quantitative maps of tissue stiffness over large regions of the liver, whereas transient ultrasound-based techniques provide localized spot measurements at limited depth in the liver in areas where there is an acoustic window. MRE is much less operator dependent than ultrasound-based techniques. The MRE sequence can require less than a minute of acquisition time. Therefore, MRE can be readily included in standard abdominal MRI protocols which can provide a comprehensive evaluation of the liver, including assessment of fat content, presence of focal disease, and of complications of chronic liver disease such as varices. MRE is has a low rate of technical failure compared to transient ultrasound elastography. The most frequent reason for technical failure in MRE is hepatic iron overload, which can decrease hepatic signal intensity in gradient echo based MRE sequences to unacceptably low levels. Despite this limitation, MRE is the only non-invasive technique that has been able to stage liver fibrosis or diagnose mild fibrosis with reasonable accuracy as reported by a recent systemic review of imaging techniques for diagnosis and staging of hepatic fibrosis (29). Studies have shown that MRE is highly reproducible in both volunteers and in patients with liver fibrosis (30-32). MRE therefore is a promising tool for detecting and staging liver fibrosis and for longitudinal assessment of response to antiviral or antifibrotic therapy. Normal liver parenchyma has shear stiffness values less than 3 kPa (23, 25, 27, 28, 37-39). Hepatic fibrosis can be diagnosed with high sensitivity and specificity if the hepatic stiffness is above this value. MRE has also been shown to be useful for differentiating between various stages of fibrosis (25, 37, 38). Liver stiffness increases incrementally with histological stage of fibrosis (Fig 7, ,88).
Fatty change in the Liver does not affect Measurement of Liver Stiffness
In patients with non- alcoholic fatty liver disease (NAFLD), steatosis alone does not appear to have a significant effect on hepatic stiffness (fig 15) (25). However, it has been shown that if the disease progresses to inflammation (non-alcoholic steatohepatitis or NASH), MRE-assessed hepatic stiffness does increase, even before the onset of fibrosis (48). More studies on utility of MRE in this particular and important cause of chronic liver disease are needed.]
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Technical considerations: Quantifying hepatic fibrosis
Fibrosis has no molecular signature that can be detected by current imaging techniques, and all imaging tests for fibrosis attempt to detect fibrosis indirectly. As collagen deposition associated with fibrosis imparts parenchymal rigidity, the leading biomarker for assessing fibrosis is through elastography. MRE uses a modified phase-contrast pulse sequence to visualize rapidly propagating mechanical shear waves (typically delivered at around 60 Hz).90 Cross-sectional elastogram images are then created depicting the stiffness generated from the wave propagation information. Technically, elastography assessments can be accomplished with most MR scanners by adding hardware to generate mechanical waves and adding specific software for acquisition and processing.90 Because the waves can be visualized and analyzed deep into the liver, MRE evaluates a large portion of the liver and can be performed in conjunction with conventional MRI.
Validity and Reliability - diagnostic accuracy and reproducibility for quantifying hepatic fibrosis
Several individual studies have investigated the diagnostic accuracy of MRE for quantifying hepatic fibrosis in NAFLD, and a recent pooled analysis of individual participant level data has demonstrated that MRE has a high diagnostic accuracy (AUC 0.90, 95% CI 0.84 - 0.94) for identifying advanced fibrosis (stage 3-4). 25, 26, 30, 91-94 (Table 3) Although the diagnostic accuracy has been demonstrated to be consistent across patient sub-groups (obesity, gender) and disease states (inflammation grade, liver stiffness), a recent prospective cohort study has demonstrated that more advanced versions of the imaging modality (3-dimensional MRE at 40Hz) are more accurate (AUC 0.981) as compared to more traditional modalities (3D-MRE at 60Hz AUC: 0.927; 2D-MRE at 40Hz AUC: 0.921).94 The inter-observer agreement in assessments for MRE has been demonstrated to be high (ICC 0.99, 95% CI 0.98 - 1.00), and the agreement for MRE assessments is higher than that with pathologist staging (ICC 0.91, 95% CI 0.86 - 0.94).95 Thus, MRE is highly accurate for detecting hepatic fibrosis, results are not influenced by patient demographics making assessments reproducible across key sub-populations, and the inter-observer agreement for staging fibrosis is nearly perfect and higher than that seen with histopathology. For these reasons, MRE is considered to be a reliable, highly accurate, and precise method for assessing hepatic fibrosis.30
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