Clinical Utility of Magnetic Resonance Imaging Biomarkers for Identifying Nonalcoholic Steatohepatitis Patients at High Risk of Progression: A Multicenter Pooled Data and Meta-Analysis.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is increasing in prevalence worldwide. NAFLD is associated with excess risk of all-cause mortality, and its progression to nonalcoholic steatohepatitis (NASH) and fibrosis accounts for a growing proportion of cirrhosis and hepatocellular cancer and thus is a leading cause of liver transplant worldwide. Noninvasive precise methods to identify patients with NASH and NASH with significant disease activity and fibrosis are crucial when the disease is still modifiable. The aim of this study was to examine the clinical utility of corrected T1 (cT1) vs magnetic resonance imaging (MRI) liver fat for identification of NASH participants with nonalcoholic fatty liver disease activity score ≥4 and fibrosis stage (F) ≥2 (high-risk NASH). METHODS: Data from five clinical studies (n = 543) with participants suspected of NAFLD were pooled or used for individual participant data meta-analysis. The diagnostic accuracy of the MRI biomarkers to stratify NASH patients was determined using the area under the receiver operating characteristic curve (AUROC). RESULTS: A stepwise increase in cT1 and MRI liver fat with increased NAFLD severity was shown, and cT1 was significantly higher in participants with high-risk NASH. The diagnostic accuracy (AUROC) of cT1 to identify patients with NASH was 0.78 (95% CI, 0.74-0.82), for liver fat was 0.78 (95% CI, 0.73-0.82), and when combined with MRI liver fat was 0.82 (95% CI, 0.78-0.85). The diagnostic accuracy of cT1 to identify patients with high-risk NASH was good (AUROC = 0.78; 95% CI, 0.74-0.82), was superior to MRI liver fat (AUROC = 0.69; 95% CI, 0.64-0.74), and was not substantially improved by combining it with MRI liver fat (AUROC = 0.79; 95% CI, 0.75-0.83). The meta-analysis showed similar performance to the pooled analysis for these biomarkers. CONCLUSIONS: This study shows that quantitative MRI-derived biomarkers cT1 and liver fat are suitable for identifying patients with NASH, and cT1 is a better noninvasive technology than liver fat to identify NASH patients at greatest risk of disease progression. Therefore, MRI cT1 and liver fat have important clinical utility to help guide the appropriate use of interventions in NAFLD and NASH clinical care pathways.

Quantitative multiparametric MRI as a non-invasive stratification tool in children and adolescents with autoimmune liver disease.

Autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC) are two very closely related autoimmune liver diseases with overlapping clinical features and similar management strategies. The purpose of this study was to assess the utility of quantitative imaging markers to distinguish ASC from AIH in paediatrics. 66 participants (N = 52 AIH, N = 14 ASC) aged 14.4 ± 3.3 years scheduled to undergo routine biopsy and baseline serum liver biochemistry testing were invited to undergo MRI (non-contrast abdominal MRI and 3D fast spin-echo MRCP). Multiparametric MRI was used to measure fibro-inflammation with corrected T1 (cT1), while the biliary tree was modelled   using quantitative MRCP (MRCP +). Mann-Whitney U tests were performed to compare liver function tests with imaging markers between patient groups (ASC vs AIH). Receiver operating characteristic curves and stepwise logistic regressions were used to identify the best combination of markers to discriminate between ASC and AIH. Correlations between liver function tests and imaging markers were performed using Spearman's rank correlation. cT1 was significantly correlated with liver function tests (range 0.33 ≤ R ≤ 56, p < 0.05), as well as with fibrosis, lobular and portal inflammation (range 0.31 ≤ R ≤ 42, p < 0.05). 19 MRCP + metrics correlated significantly with liver function tests (range 0.29 ≤ R ≤ 0.43, p < 0.05). GGT and MRCP + metrics were significantly higher in ASC compared to those with AIH. The best multivariable model for distinguishing ASC from AIH included total number of ducts and the sum of relative severity of both strictures and dilatations AUC: 0.91 (95% CI 0.78-1). Quantitative MRCP metrics are a good discriminator of ASC from AIH.

Multiparametric Magnetic Resonance Imaging, Autoimmune Hepatitis, and Prediction of Disease Activity.

Noninvasive monitoring of disease activity in autoimmune hepatitis (AIH) has potential advantages for patients for whom liver biopsy is invasive and with risk. We sought to understand the association of multiparametric magnetic resonance imaging (mpMRI) with clinical course of patients with AIH. We prospectively recruited 62 patients (median age, 55 years; 82% women) with clinically confirmed AIH. At recruitment, patients underwent mpMRI with LiverMultiScan alongside clinical investigations, which were repeated after 12-18 months. Associations between iron-corrected T1 (cT1) and other markers of disease were investigated at baseline and at follow-up. Discriminative performance of cT1, liver stiffness, and enhanced liver fibrosis (ELF) to identify those who failed to maintain remission over follow-up was investigated using the areas under the receiver operating characteristic curves (AUCs). Baseline cT1 correlated with alanine aminotransferase (Spearman's correlation coefficient [r S] = 0.28, P = 0.028), aspartate aminotransferase (r S = 0.26, P = 0.038), international normalized ratio (r S = 0.35 P = 0.005), Model for End-Stage Liver Disease (r S = 0.32, P = 0.020), ELF (r S = 0.29, P = 0.022), and liver stiffness r S = 0.51, P < 0.001). After excluding those not in remission at baseline (n = 12), 32% of the remainder failed to maintain remission during follow-up. Failure to maintain remission was associated with significant increases in cT1 over follow-up (AUC, 0.71; 95% confidence interval [CI], 0.52-0.90; P = 0.035) but not with changes in liver stiffness (AUC, 0.68; 95% CI, 0.49-0.87; P = 0.067) or ELF (AUC, 0.57; 95% CI, 0.37-0.78; P = 0.502). cT1 measured at baseline was a significant predictor of future loss of biochemical remission (AUC, 0.68; 95% CI, 0.53-0.83; P = 0.042); neither liver stiffness (AUC, 0.53; 95% CI, 0.34-0.71; P = 0.749) nor ELF (AUC, 0.52; 95% CI, 0.33-0.70; P = 0.843) were significant predictors of loss of biochemical remission. Conclusion: Noninvasive mpMRI has potential to contribute to risk stratification in patients with AIH.

Quantitative multiparametric magnetic resonance imaging can aid non-alcoholic steatohepatitis diagnosis in a Japanese cohort.

BACKGROUND: Non-invasive assessment of non-alcoholic steatohepatitis (NASH) is increasing in desirability due to the invasive nature and costs associated with the current form of assessment; liver biopsy. Quantitative multiparametric magnetic resonance imaging (mpMRI) to measure liver fat (proton density fat fraction) and fibroinflammatory disease [iron-corrected T1 (cT1)], as well as elastography techniques [vibration-controlled transient elastography (VCTE) liver stiffness measure], magnetic resonance elastography (MRE) and 2D Shear-Wave elastography (SWE) to measure stiffness and fat (controlled attenuated parameter, CAP) are emerging alternatives which could be utilised as safe surrogates to liver biopsy. AIM: To evaluate the agreement of non-invasive imaging modalities with liver biopsy, and their subsequent diagnostic accuracy for identifying NASH patients. METHODS: From January 2019 to February 2020, Japanese patients suspected of NASH were recruited onto a prospective, observational study and were screened using non-invasive imaging techniques; mpMRI with LiverMultiScan ®, VCTE, MRE and 2D-SWE. Patients were subsequently biopsied, and samples were scored by three independent pathologists. The diagnostic performances of the non-invasive imaging modalities were assessed using area under receiver operating characteristic curve (AUC) with the median of the histology scores as the gold standard diagnoses. Concordance between all three independent pathologists was further explored using Krippendorff's alpha (a) from weighted kappa statistics. RESULTS: N = 145 patients with mean age of 60 (SD: 13 years.), 39% females, and 40% with body mass index ≥ 30 kg/m2 were included in the analysis. For identifying patients with NASH, MR liver fat and cT1 were the strongest performing individual measures (AUC: 0.80 and 0.75 respectively), and the mpMRI metrics combined (cT1 and MR liver fat) were the overall best non-invasive test (AUC: 0.83). For identifying fibrosis ≥ 1, MRE performed best (AUC: 0.97), compared to VCTE-liver stiffness measure (AUC: 0.94) and 2D-SWE (AUC: 0.94). For assessment of steatosis ≥ 1, MR liver fat was the best performing non-invasive test (AUC: 0.92), compared to controlled attenuated parameter (AUC: 0.75). Assessment of the agreement between pathologists showed that concordance was best for steatosis (a = 0.58), moderate for ballooning (a = 0.40) and fibrosis (a = 0.40), and worst for lobular inflammation (a = 0.11). CONCLUSION: Quantitative mpMRI is an effective alternative to liver biopsy for diagnosing NASH and non-alcoholic fatty liver, and thus may offer clinical utility in patient management.

Multiparametric MRI as a Noninvasive Monitoring Tool for Children With Autoimmune Hepatitis.

OBJECTIVES: Autoimmune hepatitis (AIH) is a progressive liver disease managed with corticosteroids and immunosuppression and monitored using a combination of liver biochemistry and histology. However, liver biopsy is invasive with risk of pain and bleeding. The aim of the present study was to investigate the utility of noninvasive imaging with multiparametric magnetic resonance imaging (MRI) (mpMRI) to provide clinically useful information on the presence and extent of hepatic inflammation, potentially guiding immunosuppression. METHODS: Eighty-one participants (aged 6-18), 21 healthy and 60 AIH patients, underwent multiparametric MRI to measure fibro-inflammation with iron-corrected T1 (cT1) at the Children's Memorial Health Institute in Warsaw alongside other clinical blood tests and liver biopsy at recruitment and after an average of 16-month follow-up (range 9-22 months). Correlation analyses were used to investigate the associations between cT1 with blood serum markers and histological scores. RESULTS: At recruitment, patients with AIH had a higher cT1 value than healthy controls (P < 0.01). cT1 correlated significantly with key histopathological features of disease. Treatment naïve AIH patients showed evidence of inflammation and heterogeneity across the liver compared to healthy controls.At follow-up, cT1 showed utility in monitoring disease regression as most patients showed significantly reduced fibro-inflammation with treatment (P < 0.0001) over the observational period. Six patients had histological fibrosis and clear fibro-inflammation on MR despite biochemical remission (normalized aspartate aminotransferase (AST), alanine aminotransferase (ALT), and immunoglobulin G [IgG]). CONCLUSIONS: Multiparametric MRI can measure disease burden in pediatric AIH and can show changes over time in response to therapy. Active disease can be seen even in biochemical remission in children.

A composite biomarker using multiparametric magnetic resonance imaging and blood analytes accurately identifies patients with non-alcoholic steatohepatitis and significant fibrosis.

Non-alcoholic steatohepatitis (NASH) is major health burden lacking effective pharmacological therapies. Clinical trials enrol patients with histologically-defined NAFLD (non-alcoholic fatty liver disease) activity score (NAS) ≥ 4 and Kleiner-Brunt fibrosis stage (F) ≥ 2; however, screen failure rates are often high following biopsy. This study evaluated a non-invasive MRI biomarker, iron-corrected T1 mapping (cT1), as a diagnostic pre-screening biomarker for NASH. In a retrospective analysis of 86 biopsy confirmed NAFLD patients we explored the potential of blood and imaging biomarkers, both in isolation and in combination, to discriminate those who have NAS ≥ 4 and F ≥ 2 from those without. Stepwise logistic regression was performed to select the optimal combination of biomarkers, diagnostic accuracy was determined using area under the receiver operator curve and model validated confirmed with and fivefold cross-validation. Results showed that levels of cT1, AST, GGT and fasting glucose were all good predictors of NAS ≥ 4 and F ≥ 2, and the model identified the combination of cT1-AST-fasting glucose (cTAG) as far superior to any individual biomarker (AUC 0.90 [0.84-0.97]). This highlights the potential utility of the composite cTAG score for screening patients prior to biopsy to identify those suitable for NASH clinical trial enrolment.

Prognostic value of multiparametric magnetic resonance imaging, transient elastography and blood-based fibrosis markers in patients with chronic liver disease.

BACKGROUND & AIMS: Liver cT1 , liver T1 , transient elastography (TE) and blood-based biomarkers have independently been shown to predict clinical outcomes but have not been directly compared in a single cohort of patients. Our aim was to compare these tests' prognostic value in a cohort of patients with compensated chronic liver disease. METHODS: Patients with unselected compensated liver disease aetiologies had baseline assessments and were followed up for development of clinical outcomes, blinded to the imaging results. The prognostic value of non-invasive liver tests at prespecified thresholds was assessed for a combined clinical endpoint comprising ascites, variceal bleeding, hepatic encephalopathy, hepatocellular carcinoma, liver transplantation and mortality. RESULTS: One hundred and ninety-seven patients (61% male) with median age of 54 years were followed up for 693 patient-years (median (IQR) 43 (26-58) months). The main diagnoses were NAFLD (41%), viral hepatitis (VH, 25%) and alcohol-related liver disease (ArLD; 14%). During follow-up 14 new clinical events, and 11 deaths occurred. Clinical outcomes were predicted by liver cT1  > 825ms with HR 9.9 (95% CI: 1.29-76.4, P = .007), TE > 8kPa with HR 7.8 (95% CI: 0.97-62.3, P = .02) and FIB-4 > 1.45 with HR 4.09 (95% CI: 0.90-18.4, P = .05). In analysis taking into account technical failure and unreliability, liver cT1  > 825 ms could predict clinical outcomes (P = .03), but TE > 8kPa could not (P = .4). CONCLUSIONS: We provide further evidence that liver cT1 , TE and serum-based biomarkers can predict clinical outcomes, but when taking into account technical failure/unreliability, TE cut-offs perform worse than those of cT1 and blood biomarkers.

Correlations Between MRI Biomarkers PDFF and cT1 With Histopathological Features of Non-Alcoholic Steatohepatitis.

Introduction: Late stage clinical trials in non-alcoholic steatohepatitis (NASH) are currently required by the FDA to use liver biopsy as a primary endpoint. The well-reported limitations with biopsy, such as associated risks and sampling error, coupled with patient preference, are driving investigation into non-invasive alternatives. MRI-derived biomarkers proton density fat fraction (PDFF) and iron-corrected T1 mapping (cT1) are gaining traction as emerging alternatives to biopsy for NASH. Our aim was to explore the correlations between cT1 and PDFF (from LiverMultiScan®), with the histological components on the NAFLD-NASH spectrum in a large cohort of cross-sectional data, in order to calibrate the measurement to histology, and to infer what might constitute a clinically meaningful change when related to the FDA's criteria. Materials and Methods: In a retrospective analysis of data combined from three previously published observational NASH studies, in which adult participants who underwent liver biopsy on suspicion of NAFLD or NASH and had an MRI scan measuring cT1 and PDFF (LiverMultiScan®, Perspectum Ltd, UK), associations between imaging biomarkers and histology were tested using Spearman's rank correlation coefficient (rs), and further exploration of the relationships between the imaging variables and histology were performed using linear regression. Results: N = 264 patients with mean age of 54 (SD:9.9), 39% female, and 69% with BMI ≥ 30kg.m-2 were included in the analysis. cT1 and PDFF both correlated with all features of the NAFLD activity score (NAS). cT1 was also positively correlated with Kleiner-Brunt fibrosis. Partial correlations, adjusting for steatosis, revealed cT1 correlated with inflammation and fibrosis, whereas PDFF did not, and both were still associated with the NAS, but correlation was weaker with PDFF than cT1. An estimated difference of 88 ms in cT1, or 21% relative difference in PDFF was related to a two-point difference in overall NAS. Conclusion: The correlations between cT1 and PDFF with the histopathological hallmarks of NASH demonstrate the potential utility of both cT1 and PDFF as non-invasive biomarkers to detect a pharmacodynamic change in NASH, with cT1 showing superiority for detecting changes in inflammation and fibrosis, rather than liver fat alone.

Measurement of liver iron by magnetic resonance imaging in the UK Biobank population.

The burden of liver disease continues to increase in the UK, with liver cirrhosis reported to be the third most common cause of premature death. Iron overload, a condition that impacts liver health, was traditionally associated with genetic disorders such as hereditary haemochromatosis, however, it is now increasingly associated with obesity, type-2 diabetes and non-alcoholic fatty liver disease. The aim of this study was to assess the prevalence of elevated levels of liver iron within the UK Biobank imaging study in a cohort of 9108 individuals. Magnetic resonance imaging (MRI) was undertaken at the UK Biobank imaging centre, acquiring a multi-echo spoiled gradient-echo single-breath-hold MRI sequence from the liver. All images were analysed for liver iron and fat (expressed as proton density fat fraction or PDFF) content using LiverMultiScan. Liver iron was measured in 97.3% of the cohort. The mean liver iron content was 1.32 ± 0.32 mg/g while the median was 1.25 mg/g (min: 0.85 max: 6.44 mg/g). Overall 4.82% of the population were defined as having elevated liver iron, above commonly accepted 1.8 mg/g threshold based on biochemical iron measurements in liver specimens obtained by biopsy. Further analysis using univariate models showed elevated liver iron to be related to male sex (p<10(-16), r2 = 0.008), increasing age (p<10(-16), r2 = 0.013), and red meat intake (p<10(-16), r2 = 0.008). Elevated liver fat (>5.6% PDFF) was associated with a slight increase in prevalence of elevated liver iron (4.4% vs 6.3%, p = 0.0007). This study shows that population studies including measurement of liver iron concentration are feasible, which may in future be used to better inform patient stratification and treatment.