MRE combined with FIB-4 (MEFIB) index in detection of candidates for pharmacological treatment of NASH-related fibrosis

Abstract

Objective: Patients with non-alcoholic fatty liver disease (NAFLD) with ≥stage 2 fibrosis are at increased risk for liver-related mortality and are candidates for pharmacological therapies for treatment of NAFLD. The aim of this prospective cohort study is to examine the diagnostic accuracy of MR elastography (MRE) combined with fibrosis-4 (FIB-4) in diagnosing ≥stage 2 fibrosis (candidates for pharmacological therapies).

Design: This is a cross-sectional analysis of a prospective cohort (University of California at San Diego (UCSD)-NAFLD) including 238 consecutive patients with contemporaneous MRE and biopsy-proven NAFLD. Non-alcoholic steatohepatitis-Clinical Research Network-Histologic Scoring System was used to assess histology. The radiologist and pathologist were blinded to clinical, pathological and imaging data, respectively. Receiver operating characteristics (ROCs) were determined to examine the diagnostic accuracy of MRE and FIB-4 for diagnosis of ≥stage 2 fibrosis in NAFLD. We then validated these findings in an independent validation cohort derived from Yokohama City University in Japan (Japan-NAFLD Cohort; N=222 patients).

Results: In the UCSD-NAFLD (training) Cohort, MRE demonstrated a clinically significant diagnostic accuracy for the detection of ≥stage 2 fibrosis with an area under the ROC curve (AUROC) of 0.93 (95% CI 0.90 to 0.97) vs FIB-4 with an AUROC of 0.78 (95% CI 0.71 to 0.85), which was both clinically and statistically significant (p<0.0001). We then combined MRE with FIB-4 (MRE ≥3.3 kPa and FIB-4 ≥1.6) to develop a clinical prediction rule to rule in ≥stage 2 fibrosis patients which had positive predictive value (PPV) of 97.1% (p<0.02) in the UCSD-NAFLD cohort (AUROC of 0.90 (95% CI 0.85 to 0.95)) which remained significant at PPV of 91.0% (p<0.003) in the Japan-NAFLD Cohort (AUROC of 0.84 (95% CI 0.78 to 0.89)).

Conclusion: MRE combined with FIB-4 (MEFIB) index may be used for non-invasive identification of candidates for (≥stage 2 fibrosis) pharmacological therapy among patients with NAFLD with a high PPV.

Keywords: fatty liver; hepatic fibrosis; liver function test; liver imaging.

Figure 1.. Derivation of UCSD – NAFLD Cohort

Abbreviations: MRE, magnetic resonance elastography *NASH CRN Histologic Score System was used [35]

Figure 2.. MRE is more accurate than routinely available clinical prediction rule, FIB - 4

Comparison of diagnostic accuracy between MRE and FIB-4 in detecting ≥ stage 2 fibrosis in UCSD-NAFLD Cohort and Japan-NAFLD Cohort. Left: In UCSD -NAFLD Cohort, the AUROC for MRE was 0.93 which was statistically significant compared to FIB-4 which was 0.78 (p <0.0001). Right: The diagnostic accuracy of MRE (AUROC=0.89) in Japan – NAFLD Cohort was also statistically significant compared to FIB-4 (AUROC=0.79). The p value is provided. Abbreviations: MRE, magnetic resonance elastography; FIB – 4, fibrosis -4

Figure 3.. Representative patient characteristics by Magnetic Resonance Elastography (MRE) image and liver biopsy. Patient A had a FIB-4 of 1.03; patient B had a FIB-4 of 2.62.

Abbreviation: MRE, magnetic resonance elastography; FIB -4, fibrosis – 4 *Trichrome stain highlights normal collagen surrounding the central hepatic venule (no significant fibrosis, 40X magnification, patient A) and bridging fibrosis (10X magnification, patient B).