MRI biomarkers of liver disease are robust and reproducible alternatives to liver biopsy. Emerging data suggest that absolute reduction in iron corrected T1 (cT1) of ≥ 80 ms and relative reduction in liver fat content of 30% reflect histological improvement. We aimed to validate the associations of changes to these noninvasive biomarkers with histological improvement, specifically the resolution of steatohepatitis. A retrospective analysis of participants from three interventional clinical trials who underwent multiparametric MRI to measure liver cT1 and liver fat content (LFC) (LiverMultiScan) alongside biopsies at baseline and end of study. Responders were defined as those achieving resolution of steatohepatitis with no worsening in fibrosis. Differences in the magnitude of change in cT1 and LFC between responders and non-responders was assessed. Individual patient data from 150 participants were included. There was a significant decrease in liver cT1 (-119 ms vs. -49 ms) and liver fat content (-65% vs. -29%) in responders compared to non-responders (P < .001) respectively. The diagnostic accuracy to identify responders was 0.72 (AUC) for both. The Youden's index for cT1 to separate responders from non-responders was -82 ms and for liver fat was a 58% relative reduction. Those achieving a ≥ 80 ms reduction in cT1 were 5-times more likely to achieve histological response (sens 0.68; spec 0.70). Those achieving a 30% relative reduction in liver fat were ∼4 times more likely to achieve a histological response (sens 0.77; spec 0.53). These results, from three combined drug trials, demonstrate that changes in multiparametric MRI markers of liver health (cT1 and PDFF) can predict histological response for steatohepatitis following therapeutic intervention. There is great interest in identifying suitable biomarkers that can be used to replace liver biopsy, or to identify those patients who would benefit from one, in both the clinical management of MASH and in drug development. We investigated the utility of two MRI-derived non-invasive tests, iron corrected T1 mapping (cT1) and liver fat content from proton density fat fraction (PDFF), to predict histological improvement in patients who had undergone experimental treatment for MASH. Using data from 150 people who participated in one of three clinical trials, we observed that a reduction in cT1 by over 80 ms and a relative reduction in PDFF of over 58% were the optimal thresholds for change that predicted resolution of steatohepatitis. PDFF as a marker of liver fat, and cT1 as a specific measure of liver disease activity, are both effective at identifying those who are likely responding to drug interventions and experiencing improvements in overall liver health. NCT02443116, NCT03976401, NCT03551522.

Biomarkers have the potential to accelerate drug development, as early indicators of improved clinical response, to improve patient safety, and for personalised medicine. However, few have been approved through the biomarker qualification pathways of the regulatory agencies. This paper outlines how biomarkers can accelerate drug development, and reviews the lessons learned by the EU IMI2-funded LITMUS consortium, which has had several interactions with regulatory agencies in both the US and EU regarding biomarker qualification in patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Sharing knowledge of such interactions with the scientific community is of paramount importance to increase the chances of qualification of relevant biomarkers that may accelerate drug development, and thereby help patients, across disease indications. A qualified biomarker enables a decision to be made that all understand and support in a common framework.

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.

Background and Aims: The performance of non‐invasive liver tests (NITs) is known to vary across settings and subgroups. We systematically evaluated whether the performance of three NITs in detecting advanced fibrosis in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) varies with age, sex, body mass index (BMI), type 2 diabetes mellitus (T2DM) status or liver enzymes.Methods: Data from 586 adult LITMUS Metacohort participants with histologically characterised MASLD were included. The diagnostic performance of the Fibrosis‐4 Index (FIB‐4), enhanced liver fibrosis (ELF) and vibration‐controlled transient elastography liver stiffness measurement (VCTE LSM) was evaluated. Performance was expressed as the area under the receiver operating characteristics curve (AUC). Thresholds for detecting advanced fibrosis (≥F3) were calculated for each NIT for fixed (high) sensitivity, specificity and predictive values.Results: Differences in AUC between all subgroups were small and statistically not significant, indicating comparable performance in detecting ≥F3, irrespective of these clinical factors. However, different thresholds were needed to achieve the same level of accuracy with each test. For example, for a fixed sensitivity and specificity, the thresholds for all three NITs were higher in patients with T2DM. Effects for sex, age and liver enzymes were less pronounced.Conclusions: Performance of the selected NITs in detecting advanced liver fibrosis does not vary substantially with clinical characteristics. However, different thresholds have to be selected to achieve the same sensitivity, specificity and predictive values in the respective subgroups. Large prospective studies are called for to study NIT accuracy considering multiple patient characteristics.

Background: Increasing prevalence of metabolic dysfunction–associated liver disease (MASLD) and metabolic dysfunction–associated steatohepatitis (MASH) poses a growing healthcare burden. Noninvasive diagnostic tools to replace liver biopsy are urgently needed. We investigated the utility and cost-effectiveness of including multiparametric magnetic resonance imaging (mpMRI) to the management of adults with suspected MASLD multi-nationally. Methods: RADIcAL-1, a 1:1 randomised controlled trial (standard-of-care [SoC] vs. imaging arm [IA; SoC+mpMRI]) included 802 participants from Germany, Netherlands, Portugal and UK. Wilcoxon-rank tests were used to compare access to healthcare practitioners, patient assessments and proportion of patients with a diagnosis (%diagnosis). Liver fat and disease activity (corrected T1 [cT1]) were used to identify patients not requiring biopsy in the imaging arm. Primary endpoint was mpMRI cost-effectiveness and improvement in resource use (visits avoided) using mpMRI. Results: mpMRI is cost-effective with an ICER of €4968/QALY gained. 403 were randomised to IA and 399 to SoC. SoC has significantly more specialist appointments (p = 0.015) and patient assessments (p < 0.001). Across all involved hospitals, %diagnosis is significantly higher in the imaging arm (p = 0.0012). cT1 correctly classifies 50% of patients without MASH with fibrosis and can avoid biopsy. Including all costs, the imaging arm incurs higher short-term per-patient healthcare expenditure compared to the SoC arm (€1,300 vs. €830). Conclusion: Adding mpMRI to SoC for the management of adults with suspected MASLD multi-nationally is cost-effective, enhances rate of diagnosis multi-nationally and increases rate of diagnosis without increasing other liver-related health care resource use. Due to the need for standardisation of SoC, widespread use can support optimisation of the MASLD clinical pathway and improve long-term patient management.

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.