Quantitative MRI for Monitoring Metabolic Dysfunction-Associated Steatotic Liver Disease: A Test-Retest Repeatability Study.

BACKGROUND: Quantitative magnetic resonance imaging metrics iron-corrected T1 (cT1) and liver fat from proton density fat-fraction (PDFF) are both commonly used as noninvasive biomarkers for metabolic dysfunction-associated steatohepatitis (MASH); however, their repeatability in this population has rarely been characterized. PURPOSE: To quantify the variability of cT1 and liver fat fraction from PDFF in patients with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH. STUDY TYPE: Prospective, single center. POPULATION: Twenty-one participants (female = 11, mean age 53 ± 24 years) with biopsy-confirmed MASLD, including 6 with MASH and fibrosis ≥2. FIELD STRENGTH/SEQUENCE: 3 T; T1 and T2* mapping for the generation of cT1 (shMOLLI: CardioMaps and 2D MDE, T1map-FIESTA and LMS MOST: StarMap, 2D Multi-Echo FSPGR) and magnitude-only PDFF sequence for liver fat quantification (LMS IDEAL: StarMap, 2D Multi-Echo FSPGR). ASSESSMENT: T1 mapping and PDFF scans were performed twice on the same day for all participants (N = 21), with an additional scan 2-4 weeks later for MASH patients with fibrosis ≥2 (N = 6). Whole liver segmentation masks were generated semi-automatically and average pixel counts within these masks were used for the calculation of cT1 and liver fat fraction. STATISTICAL TESTS: Bland-Altman analysis for repeatability coefficient (RC) and 95% limits of agreement (LOA) and intraclass correlation coefficient (ICC). RESULTS: Same-day RC was 32.1 msec (95% LOA: -36.6 to 24.2 msec) for cT1 and 0.6% (95% LOA: -0.5% to 0.7%) for liver fat fraction; the ICCs were 0.98 (0.96-0.99) and 1.0, respectively. Short-term RC was 65.2 msec (95% LOA: -63.8 to 76.5 msec) for cT1 and 2.6% (95% LOA: -2.8% to 3.1%) for liver fat fraction. DATA CONCLUSION: In participants with MASLD and MASH, cT1 and liver fat fraction measurements show excellent test-retest repeatability, supporting their use in monitoring MASLD and MASH. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Decreases in cT1 and liver fat content reflect treatment-induced histological improvements in MASH.

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. IMPACT AND IMPLICATIONS: 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. CLINICAL TRIAL NUMBER(S): NCT02443116, NCT03976401, NCT03551522.

MRI-serum-based score accurately identifies patients undergoing liver transplant without rejection avoiding the need for liver biopsy: A multisite European study.

Serum liver tests (serum tests) and histological assessment for T-cell-mediated rejection are essential for post-liver transplant monitoring. Liver biopsy carries a risk of complications that are preferably avoided in low-risk patients. Multiparametric magnetic resonance imaging (mpMRI) is a reliable noninvasive diagnostic method that quantifies liver disease activity and has prognostic utility. Our aim was to determine whether using mpMRI in combination with serum tests could noninvasively identify low-risk patients who underwent liver transplants who are eligible to avoid invasive liver biopsies. In a multicenter prospective study (RADIcAL2), including 131 adult and pediatric (children and adolescent) patients with previous liver transplants from the Netherlands, Portugal, and the United Kingdom, concomitant mpMRI and liver biopsies were performed. Biopsies were centrally read by 2 expert pathologists. T-cell-mediated rejection was assessed using the BANFF global assessment. Diagnostic accuracy to discriminate no rejection versus indeterminate or T-cell-mediated liver transplant rejection was performed using the area under the receiver operating characteristic curve. In this study, 52% of patients received a routine (protocol) biopsy, while 48% had a biopsy for suspicion of pathology. Thirty-eight percent of patients had no rejection, while 62% had either indeterminate (21%) or T-cell-mediated rejection (41%). However, there was a high interobserver variability (0 < Cohen's Kappa < 0.85) across all histology scores. The combined score of mpMRI and serum tests had area under the receiver operating characteristic curve 0.7 (negative predictive value 0.8) to identify those without either indeterminate or T-cell-mediated rejection. Combining both imaging and serum biomarkers into a composite biomarker (imaging and serum biomarkers) has the potential to monitor the liver graft to effectively risk stratify patients and identify those most likely to benefit from a noninvasive diagnostic approach, reducing the need for liver biopsy.

The effectiveness of magnetic resonance imaging (MRI) iron corrected T1 in monitoring metabolic dysfunction-associated steatohepatitis in obesity following bariatric surgery and lifestyle modification: a prospective cohort study.

Background: Bariatric surgery and lifestyle modification are important treatments for obesity, a risk factor for metabolic dysfunction-associated steatohepatitis (MASH). Studies have related weight reduction with changes in MASH, however, few have used imaging to investigate effects on liver health. We evaluated differences in liver response to obesity treatment using disease activity iron corrected T1 (cT1) and proton density fat fraction (PDFF) in patients with both obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: Thirty-four patients with obesity and MASLD were recruited between March 2019 to February 2022 from a tertiary hospital in this longitudinal study; 13 underwent laparoscopic sleeve gastrectomy (LSG) alongside intraoperative liver biopsy, and 21 underwent a 4-month lifestyle modification program (LMP). All patients had multi-parametric magnetic resonance imaging (MRI) at baseline and 4-months. Diagnostic accuracy to identify MASH was assessed using the area under receiver operating characteristic (AUROC) curve. Results: Four (31%) of patients in the LSG group had MASH [non-alcoholic steatohepatitis (NAS) activity score ≥4] on liver biopsy. PDFF and cT1 correlated with the NAS activity score [r=0.81, 95% confidence interval (CI): 0.453 to 0.943, P<0.001] and (r=0.70, 95% CI: 0.228 to 0.907, P=0.008, respectively). There was good AUROC curve for cT1 (0.89, 95% CI: 0.67 to 1.00, P=0.031) and PDFF (0.83, 95% CI: 0.57 to 1.00, P=0.064) to identify MASH. At follow-up, weight reduction -22.8% (P=0.013) vs. -1.3% (P=0.262) resulted in cT1 reduction of -8.04% (864 ms, P=0.025) vs. -3.87% (907 ms, P=0.083) in the LSG vs. LMP group, respectively. Significant differences between interventions were observed for percentage PDFF decrease (-64.52% vs. -29.16%, P=0.001). Both biomarkers were significantly reduced in the LSG group (cT1 by -8.04%, P=0.025, PDFF by -64.52%, P=0.012), while only PDFF (-29.16%, P=0.012) was significantly reduced in the LMP group. Conclusions: MRI biomarkers may have some utility to monitor MASH following intervention in patients with obesity allowing objective comparison between intervention strategies. Compared to LMP, LSG was more effective in improving liver health.

Quantitative digital pathology enables automated and quantitative assessment of inflammatory activity in patients with autoimmune hepatitis.

Background: Chronic liver disease diagnoses depend on liver biopsy histopathological assessment. However, due to the limitations associated with biopsy, there is growing interest in the use of quantitative digital pathology to support pathologists. We evaluated the performance of computational algorithms in the assessment of hepatic inflammation in an autoimmune hepatitis in which inflammation is a major component. Methods: Whole-slide digital image analysis was used to quantitatively characterize the area of tissue covered by inflammation [Inflammation Density (ID)] and number of inflammatory foci per unit area [Focal Density (FD)] on tissue obtained from 50 patients with autoimmune hepatitis undergoing routine liver biopsy. Correlations between digital pathology outputs and traditional categorical histology scores, biochemical, and imaging markers were assessed. The ability of ID and FD to stratify between low-moderate (both portal and lobular inflammation ≤1) and moderate-severe disease activity was estimated using the area under the receiver operating characteristic curve (AUC). Results: ID and FD scores increased significantly and linearly with both portal and lobular inflammation grading. Both ID and FD correlated moderately-to-strongly and significantly with histology (portal and lobular inflammation; 0.36≤R≤0.69) and biochemical markers (ALT, AST, GGT, IgG, and gamma globulins; 0.43≤R≤0.57). ID (AUC: 0.85) and FD (AUC: 0.79) had good performance for stratifying between low-moderate and moderate-severe inflammation. Conclusion: Quantitative assessment of liver biopsy using quantitative digital pathology metrics correlates well with traditional pathology scores and key biochemical markers. Whole-slide quantification of disease can support stratification and identification of patients with more advanced inflammatory disease activity.

Intrapancreatic fat deposition is unrelated to liver steatosis in metabolic dysfunction-associated steatotic liver disease.

Background & Aims: Individuals with obesity may develop intrapancreatic fat deposition (IPFD) and fatty pancreas disease (FPD). Whether this causes inflammation and fibrosis and leads to pancreatic dysfunction is less established than for liver damage in metabolic dysfunction-associated steatotic liver disease (MASLD). Moreover, the interrelations of FPD and MASLD are poorly understood. Therefore, we aimed to assess IPFD and fibro-inflammation in relation to pancreatic function and liver disease severity in individuals with MASLD. Methods: Seventy-six participants from the Amsterdam MASLD-MASH cohort (ANCHOR) study underwent liver biopsy and multiparametric MRI of the liver and pancreas, consisting of proton-density fat fraction sequences, T1 mapping and intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI). Results: The prevalence of FPD was 37.3%. There was a clear correlation between pancreatic T1 relaxation time, which indicates fibro-inflammation, and parameters of glycemic dysregulation, namely HbA1c (R = 0.59; p <0.001), fasting glucose (R = 0.51; p <0.001) and the presence of type 2 diabetes (mean 802.0 ms vs. 733.6 ms; p <0.05). In contrast, there was no relation between IPFD and hepatic fat content (R = 0.03; p = 0.80). Pancreatic IVIM diffusion (IVIM-D) was lower in advanced liver fibrosis (p <0.05) and pancreatic perfusion (IVIM-f), reflecting vessel density, inversely correlated to histological MASLD activity (p <0.05). Conclusions: Consistent relations exist between pancreatic fibro-inflammation on MRI and endocrine function in individuals with MASLD. However, despite shared dysmetabolic drivers, our study suggests IPFD is a separate pathophysiological process from MASLD. Impact and implications: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and 68% of people with type 2 diabetes have MASLD. However, fat infiltration and inflammation in the pancreas are understudied in individuals with MASLD. In this cross-sectional MRI study, we found no relationship between fat accumulation in the pancreas and liver in a cohort of patients with MASLD. However, our results show that inflammatory and fibrotic processes in the pancreas may be interrelated to features of type 2 diabetes and to the severity of liver disease in patients with MASLD. Overall, the results suggest that pancreatic endocrine dysfunction in individuals with MASLD may be more related to glucotoxicity than to lipotoxicity. Clinical trial number: NTR7191 (Dutch Trial Register).

Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol.

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721.

Multiparametric Magnetic Resonance Imaging and Magnetic Resonance Elastography to Evaluate the Early Effects of Bariatric Surgery on Nonalcoholic Fatty Liver Disease.

Background: Bariatric surgery is the most effective treatment for morbid obesity and reduces the severity of nonalcoholic fatty liver disease (NAFLD) in the long term. Less is known about the effects of bariatric surgery on liver fat, inflammation, and fibrosis during the early stages following bariatric surgery. Aims: This exploratory study utilises advanced imaging methods to investigate NAFLD and fibrosis changes during the early metabolic transitional period following bariatric surgery. Methods: Nine participants with morbid obesity underwent sleeve gastrectomy. Multiparametric MRI (mpMRI) and magnetic resonance elastography (MRE) were performed at baseline, during the immediate (1 month), and late (6 months) postsurgery period. Liver fat was measured using proton density fat fraction (PDFF), disease activity using iron-correct T1 (cT1), and liver stiffness using MRE. Repeated measured ANOVA was used to assess longitudinal changes and Dunnett's method for multiple comparisons. Results: All participants (Age 45.1 ± 9.0 years, BMI 39.7 ± 5.3 kg/m2) had elevated hepatic steatosis at baseline (PDFF >5%). In the immediate postsurgery period, PDFF decreased significantly from 14.1 ± 7.4% to 8.9 ± 4.4% (p = 0.016) and cT1 from 826.9 ± 80.6 ms to 768.4 ± 50.9 ms (p = 0.047). These improvements continued to the later postsurgery period. Bariatric surgery did not reduce liver stiffness measurements. Conclusion: Our findings support using MRI as a noninvasive tool to monitor NAFLD in patient with morbid obesity during the early stages following bariatric surgery.

NAFLD and NASH biomarker qualification in the LITMUS consortium - Lessons learned.

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.

Brain signal complexity in adults with Down syndrome: Potential application in the detection of mild cognitive impairment.

Background: Down syndrome (DS) is considered the most frequent cause of early-onset Alzheimer's disease (AD), and the typical pathophysiological signs are present in almost all individuals with DS by the age of 40. Despite of this evidence, the investigation on the pre-dementia stages in DS is scarce. In the present study we analyzed the complexity of brain oscillatory patterns and neuropsychological performance for the characterization of mild cognitive impairment (MCI) in DS. Materials and methods: Lempel-Ziv complexity (LZC) values from resting-state magnetoencephalography recordings and the neuropsychological performance in 28 patients with DS [control DS group (CN-DS) (n = 14), MCI group (MCI-DS) (n = 14)] and 14 individuals with typical neurodevelopment (CN-no-DS) were analyzed. Results: Lempel-Ziv complexity was lowest in the frontal region within the MCI-DS group, while the CN-DS group showed reduced values in parietal areas when compared with the CN-no-DS group. Also, the CN-no-DS group exhibited the expected pattern of significant increase of LZC as a function of age, while MCI-DS cases showed a decrease. The combination of reduced LZC values and a divergent trajectory of complexity evolution with age, allowed the discrimination of CN-DS vs. MCI-DS patients with a 92.9% of sensitivity and 85.7% of specificity. Finally, a pattern of mnestic and praxic impairment was significantly associated in MCI-DS cases with the significant reduction of LZC values in frontal and parietal regions (p = 0.01). Conclusion: Brain signal complexity measured with LZC is reduced in DS and its development with age is also disrupted. The combination of both features might assist in the detection of MCI within this population.