To develop an accurate and precise liver 3DT 1 $$ {T}_1 $$ mapping method using only scanner-agnostic sequences.

While the spoiled gradient-recalled echo sequence is widely available on clinical scanners, variable flip angleT 1 $$ {T}_1 $$ mapping methods based on this sequence provide biasedT 1 $$ {T}_1 $$ estimates, with the largest systematic error arising fromB 1 + $$ {B}_1^{+} $$ inhomogeneities. To correct for this, the flip angle was mapped using a 2D gradient-echo double-angle method approach. To correct for the confounding effect of fat on liverT 1 $$ {T}_1 $$ andB 1 + $$ {B}_1^{+} $$ , Dixon and fat saturation techniques were used in combination with the variable flip angle and theB 1 + $$ {B}_1^{+} $$ map acquisitions, respectively. TheT 1 $$ {T}_1 $$ andB 1 + $$ {B}_1^{+} $$ mapping methods were validated with aT 1 $$ {T}_1 $$ -phantom against gold standard methods. An intra- and inter-repeatability study was conducted at 3T in 10 healthy individuals' livers.

The developed 3DT 1 $$ {T}_1 $$ mapping method achieved an excellent agreement with the gold standard, with a weighted root mean squared normalized error below 2.8%. In vivo, a medianT 1 $$ {T}_1 $$ standard deviation of 31 ms and an interquartile range of [27, 39] ms was achieved across all measurements, including the intra- and inter-repeatability study data. A within-subject standard deviation forT 1 $$ {T}_1 $$ of 21 ± 5 ms had a corresponding repeatability coefficient of 60 ms. The measuredT 1 $$ {T}_1 $$ values agree well with MOLLI and SASHAT 1 $$ {T}_1 $$ mapping methods, with averageT 1 $$ {T}_1 $$ differences of 5%.

Accurate and precise 3DT 1 $$ {T}_1 $$ liver measurements can lead the way to the wider adoption of a clinically feasibleT 1 $$ {T}_1 $$ measurement as a marker of hepatic fibro-inflammation.

To identify abdominal contrast magnetic resonance imaging (MRI) features associated with histopathological severity, and treatment response in autoimmune hepatitis (AIH).

AIH patients who had abdominal contrast MRI within 3 months of liver biopsy were retrospectively enrolled. Histopathological severity, liver volume, MRI features, laboratory tests, and treatment response were collected. MRI and serum models were constructed through stepwise univariate and multivariate logistic regression for diagnosing severe histopathology and predicting insufficient response (IR).

One hundred AIH patients were included (median age: 57.0 years, 79.0% female). For diagnosing severe portal inflammation, reticular fibrosis and volume ratio of segment V-VIII to total liver (SV-SVIII/TLV) achieved an area under the receiver operating characteristic curve (AUROC) of 0.765 (95% CI 0.670-0.860). Severe confluent necrosis was modeled using hepatic fissure widening, reticular fibrosis, and volume ratio of segment I-III to segments IV-VIII, achieving an AUROC of 0.796 (95% CI 0.708-0.885). Severe histological activity was modeled using ascites, and SV-SVIII/TLV achieved an AUROC of 0.748 (95% CI 0.649-0.847). To diagnose cirrhosis, ascites, reticular fibrosis, and the volume ratio of segment I to the total liver were employed, yielding an AUROC of 0.833 (95% CI 0.716-0.949); IR (transaminases and/or immunoglobulin G remaining unnormal after 6 months of immunosuppressive treatment) was modeled using ascites, gallbladder wall edema, and transient hepatic attenuation difference, achieving an AUROC of 0.796 (95% CI 0.691-0.902).

The MRI models demonstrated relatively good performance in evaluating histopathological severity and treatment response. Combining MRI and serum models could enhance diagnostic and prognostic efficacy.

Question Abdominal contrast MRI may help clinicians better evaluate the histopathological severity and treatment response of autoimmune hepatitis (AIH), but there is currently limited research. Findings Models based on MRI features perform well in diagnosing severe portal inflammation, confluent necrosis, histological activity, and cirrhosis, as well as predicting insufficient response. Clinical relevance Abdominal contrast MRI, combined with serological parameters, provides a new and stronger noninvasive method for clinically assessing AIH progression and treatment.

Liver fibrosis is an inevitable stage in the progression of most chronic liver diseases. Early diagnosis and treatment of liver fibrosis are crucial for effectively managing chronic liver conditions. However, there lacks a noninvasive and sensitive imaging method capable of early assessing fibrosis activity. Here, we report a molecular magnetic resonance imaging (MRI) probe for imaging fibroblast activation protein (FAP), which is overexpressed on activated hepatic stellate cells (HSCs) even in very early fibrotic livers. This method relies on FAP-catalyzed in situ self-assembly of its substrate probe that leads to the increase of the rotational correlation time (τR) of probe, thereby notably amplifies T1 MRI signal. Thanks to the superior specificity and efficiency of enzymatic reaction, our method has been validated as highly selective and sensitive to FAP in two liver fibrosis mouse models. By establishing a direct correlation between MRI signals and fibrosis activity, our method enables continuous monitoring of liver fibrotic disease progression and assessment of treatment responses.

T1 relaxation time is a tissue-specific parameter that correlates with liver fibrosis, and can be a valuable tool for detecting and staging of liver disease. However, T1 can be affected by histological factors such as fat, so it is necessary to study the effects of hepatic steatosis when assessing liver function and fibrosis. The purpose of this study is to investigate the fat separation effect of T1 mapping using Dixon watermap Look-Locker inversion recovery (LLIR) in the assessment of liver function on gadoxetic acid (GA)-enhanced magnetic resonance imaging (MRI).

A total of 226 patients who underwent 3T MRI, including a 2D Dixon fat-separated LLIR T1 mapping, were included retrospectively. Two independent readers measured pre- and post-contrast T1 relaxation times (preT1 and postT1) on composite and watermap T1, and reproducibility was evaluated. The correlation of T1 parameters with biochemical and imaging biomarkers of liver function were assessed on both composite and Dixon watermap images; T1 parameters included averaged preT1, postT1 values, changes between pre- and post-T1liver (deltaT1) and adjusted T1liver (postT1liver - T1spleen/T1spleen). And the diagnostic performance of T1 parameters for Child-Pugh (CP) class was also evaluated.

Inter- and intra-reader reproducibility showed almost perfect agreement [intraclass correlation coefficient (ICC) 0.929-0.999]. Watermap preT1 (r=-0.125, P=0.068) and watermap deltaT1 (r=0.055, P=0.414) showed loss of correlation with fat fraction (FF) compared with preT1 and deltaT1. Albumin, total bilirubin (TB), hepatobiliary enhancement grade, and R2* (1/T2*), were significantly associated with watermap T1, eliminating the effect of FF. Area under the curve (AUC) of preT1, watermap preT1, deltaT1, postT1, watermap adjusted T1, and adjusted T1 were 0.681 [standard error (SE) 0.114], 0.748 (SE 0.098), 0.921 (SE 0.033), 0.951 (SE 0.018), 0.950 (SE 0.018), and 0.973 (SE 0.013) respectively, for differentiating patient with CP class B/C from CP-A/chronic liver disease (CLD).

T1 values using Dixon watermap LLIR eliminated the confounding effect of fat and showed the correlation with serological and imaging markers of liver function. Adjusted T1, watermap adjusted T1, and postT1 showed the highest diagnostic performance in differentiating CP class B/C from CP-A/CLD.

Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis of unknown etiology that predominantly affects young children. The objective of this study was to investigate the correlation between myocardial and hepatic native T1 value and myocardial late gadolinium enhancement (LGE) in pediatric patients with KD.

In this cross-sectional retrospective study, 115 KD patients (50 in the acute phase, 65 in the chronic phase) and 40 age- and gender-matched controls underwent cardiac magnetic resonance (CMR) imaging with T1 mapping and LGE sequences. KD patients were subgrouped based on the myocardial LGE. Cardiac and hepatic T1 value as well as laboratory tests were also analyzed.

Both cardiac and hepatic T1 value were significantly elevated in KD patients compared to controls, with the highest values noted in the acute phase (myocardial 1,393±70, 1,345±65, 1,303±62 ms; hepatic 813±25, 787±29, 758±38 ms; P=0.001, P=0.001, respectively). KD patients with myocardial LGE had significantly higher myocardial and hepatic T1 value in both the acute (1,442±66, 1,381±67 ms; 836±47, 803±30 ms, P=0.048, P=0.013, respectively) and chronic phases (myocardial 1,393±91, 1,331±50 ms; hepatic 811±39, 780±21 ms, P=0.012, P=0.001, respectively). Multivariate analysis demonstrated a significant correlation between the disease phase, albumin, and hepatic T1 value in KD patients. The combined of myocardial and hepatic T1 value significantly enhances the diagnostic performance of myocardial LGE, increasing the area under the curve (AUC) from 0.773 to 0.881 (P=0.013).

Elevated myocardial and hepatic T1 values correlate with myocardial LGE in KD, highlighting systemic involvement. The integration of these T1 values enhances the non-invasive diagnosis of myocardial involvement in KD, demonstrating their utility in assessing disease severity and progression.

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.

Cirrhosis is a major cause of morbidity and mortality; however, there are no approved therapies except orthotopic liver transplantation. Preclinical studies showed that bone-marrow-derived macrophage injections reduce inflammation, resolve fibrosis and stimulate liver regeneration. In a multicenter, open-label, parallel-group, phase 2 randomized controlled trial ( ISRCTN10368050 ) in n = 51 adult patients with compensated cirrhosis and Model for End-Stage Liver Disease (MELD) score ≥10 and ≤17, we evaluated the efficacy of autologous monocyte-derived macrophage therapy (n = 27) compared to standard medical care (n = 24). The primary endpoint was the difference in baseline to day 90 change in MELD score (ΔMELD) between treatment and control groups (ΔΔMELD). Secondary endpoints included adverse clinical outcomes, non-invasive fibrosis biomarkers and health-related quality of life (HRQoL) at 90 d, 180 d and 360 d. The ΔΔMELD between day 0 and day 90 in the treatment group compared to controls was -0.87 (95% confidence interval: -1.79, 0.0; P = 0.06); therefore, the primary endpoint was not met. During 360-d follow-up, five of 24 participants in the control group developed a total of 10 severe adverse events, four of which were liver related, and three deaths (two liver related), whereas no liver-related severe adverse events or deaths occurred in the treatment group. Although no differences were observed in biomarkers or HRQoL, exploratory analysis showed anti-inflammatory serum cytokine profiles after macrophage infusion. This study reinforces the safety and potential efficacy of macrophage therapy in cirrhosis, supporting further investigation.

In managing metabolic dysfunction-associated steatotic liver disease, which affects over 30% of the general population, effective noninvasive biomarkers for assessing disease severity, monitoring disease progression, predicting the development of liver-related complications, and assessing treatment response are crucial. The advantage of simple fibrosis scores lies in their widespread accessibility through routinely performed blood tests and extensive validation in different clinical settings. They have shown reasonable accuracy in diagnosing advanced fibrosis and good performance in excluding the majority of patients with a low risk of liver-related complications. Among patients with elevated serum fibrosis scores, a more specific fibrosis and imaging biomarker has proved useful to accurately identify patients at risk of liver-related complications. Among specific fibrosis blood biomarkers, enhanced liver fibrosis is the most widely utilized and has been approved in the United States as a prognostic biomarker. For imaging biomarkers, the availability of vibration-controlled transient elastography has been largely improved over the past years, enabling the use of liver stiffness measurement (LSM) for accurate assessment of significant and advanced fibrosis, and cirrhosis. Combining LSM with other routinely available blood tests enhances the ability to diagnose at-risk metabolic dysfunction-associated steatohepatitis and predict liver-related complications, some reaching an accuracy comparable to that of liver biopsy. Magnetic resonance imaging-based modalities provide the most accurate quantification of liver fibrosis, though the current utilization is limited to research settings. Expanding their future use in clinical practice depends on factors such as cost and facility availability.

Quantitative abdominal magnetic resonance imaging (MRI) offers non-invasive, objective assessment of diseases in the liver, pancreas, and other organs and is increasingly being used in the pediatric population. Certain quantitative MRI techniques, such as liver proton density fat fraction (PDFF), R2* mapping, and MR elastography, are already in wide clinical use. Other techniques, such as liver T1 mapping and pancreas quantitative imaging methods, are emerging and show promise for enhancing diagnostic sensitivity and treatment monitoring. Quantitative imaging techniques have historically required a breath-hold, making them more difficult to implement in the pediatric population. However, technological advances, including free-breathing techniques and compressed sensing imaging, are making these techniques easier to implement. The purpose of this article is to review current liver and pancreas quantitative techniques and to provide a practical guide for implementing these techniques in pediatric practice. Future directions of liver and pancreas quantitative imaging will be briefly discussed.

Autoimmune hepatitis is a rare chronic liver disease, associated with a high level of morbidity and high mortality; approximately 40% of patients with severe untreated disease die within 6 months of diagnosis. It should be treated to achieve complete biochemical and histologic resolution of the disease using corticosteroids and immunosuppression to prevent further progression to cirrhosis. The use of invasive liver biopsy is recommended for the staging and assessment of inflammation and fibrosis for treatment decision-making in the face of an unsatisfactory response or clinical remission, including being a determinant for withdrawal of immunosuppression. On the other hand, liver biopsy is invasive, costly, and not free of complications. It also has potential sampling error and poor interobserver agreement. The limitations of liver biopsy highlight the importance of developing new imaging biomarkers that allow accurate and non-invasive assessment of autoimmune hepatitis in terms of liver inflammation and fibrosis, developing the virtual biopsy concept. Therefore, we review the state-of-the-art of Magnetic Resonance Imaging sequences for the noninvasive evaluation of autoimmune hepatitis, including historical advances and future directions.

Efficient abdominal coverage with T1-mapping methods currently available in the clinic is limited by the breath hold period (BHP) and the time needed for T1 recovery. This work develops a T1-mapping framework for efficient abdominal coverage based on rapid T1 recovery curve (T1RC) sampling, slice-selective inversion, optimized slice interleaving, and a convolutional neural network (CNN)-based T1 estimation. The effect of reducing the T1RC sampling was evaluated by comparing T1 estimates from T1RC ranging from 0.63 to 2.0 s with reference T1 values obtained from T1RC = 2.5-5 s. Slice interleaving methodologies were evaluated by comparing the T1 variation in abdominal organs across slices. The repeatability of the proposed framework was demonstrated by performing acquisition on test subjects across imaging sessions. Analysis of in vivo data based on retrospectively shortening the T1RC showed that with the CNN framework, a T1RC = 0.84 s yielded T1 estimates without significant changes in mean T1 (p > 0.05) or significant increase in T1 variability (p > 0.48) compared to the reference. Prospectively acquired data using T1RC = 0.84 s, an optimized slice interleaving scheme, and the CNN framework enabled 21 slices in a 20 s BHP. Analyses across abdominal organs produced T1 values within 2% of the reference. Repeatability experiments yielded Pearson's correlation, repeatability coefficient, and coefficient of variation of 0.99, 2.5%, and 0.12%, respectively. The proposed T1 mapping framework provides full abdominal coverage within a single BHP.

To characterize T1 relaxation times of the pancreas, liver, and spleen in children with and without abdominal pathology.

This retrospective study included pediatric patients (< 18-years-old). T1 mapping was performed with a Modified Look-Locker Inversion Recovery sequence. Patients were grouped based on review of imaging reports and electronic medical records. The Kruskal-Wallis test with Dunn's multiple comparison was used to compare groups.

220 participants were included (mean age: 11.4 ± 4.2 years (1.5 T); 10.9 ± 4.5 years (3 T)). Pancreas T1 (msec) was significantly different between subgroups at 1.5 T (p < 0.0001). Significant pairwise differences included: normal (median: 583; IQR: 561-654) vs. acute pancreatitis (731; 632-945; p = 0.0024), normal vs. chronic pancreatitis (700; 643-863; p = 0.0013), and normal vs. acute + chronic pancreatitis (1020; 897-1099; p < 0.0001). Pancreas T1 was also significantly different between subgroups at 3 T (p < 0.0001). Significant pairwise differences included: normal (779; 753-851) vs. acute pancreatitis (1087; 910-1259; p = 0.0012), and normal vs. acute + chronic pancreatitis (1226; 1025-1367; p < 0.0001). Liver T1 was significantly different between subgroups only at 3 T (p = 0.0011) with pairwise differences between normal (818, 788-819) vs. steatotic (959; 848-997; p = 0.0017) and normal vs. other liver disease (882; 831-904; p = 0.0455). Liver T1 was weakly correlated with liver fat fraction at 1.5 T (r = 0.39; 0.24-0.52; p < 0.0001) and moderately correlated at 3 T (r = 0.64; 0.49-0.76; p < 0.0001). There were no significant differences in splenic T1 relaxation times between subgroups.

Pancreas T1 relaxation times are higher at 1.5 T and 3 T in children with pancreatitis and liver T1 relaxation times are higher in children with steatotic and non-steatotic chronic liver disease at 3 T.

There is an unmet clinical need for non-invasive imaging biomarkers that could replace liver biopsy in the management of patients with autoimmune hepatitis (AIH). In this study, we sought to evaluate the diagnostic accuracy of a simple uncorrected, non-contrast T1 mapping for detecting fibrosis and inflammation in AIH patients using histopathology as a reference standard.

Over 3 years, 33 patients with AIH were prospectively studied using a multiparametric liver MRI protocol which included T1 mapping. Biopsies were performed up to 3 months before imaging, and a standardized histopathological score for fibrosis (F0-F4) and inflammatory activity (PPA0-4) was used as a reference. Statistical analysis included independent t test, Mann-Whitney U-test, and ROC (receiver operating characteristic) analysis.

T1 mapping values were significantly higher in patients with advanced fibrosis (F0-2 vs. F3-4; p < 0.015), significant fibrosis (F0-1 vs. F2-4; p < 0.005), and significant inflammatory activity (PPA 0-1 vs. PPA 2-4 p = 0.048). Moreover, the technique demonstrated a good diagnostic performance in detecting significant (AUC 0.856) and advanced fibrosis (AUC 0.835), as well as significant inflammatory activity (AUC 0.763).

A rapid, simple, uncorrected, non-contrast T1 mapping sequence showed satisfactory diagnostic performance in comparison with histopathology for detecting significant tissue inflammation and fibrosis in AIH patients, being a potential non-invasive imaging biomarker for monitoring disease activity in such individuals.

Crohn's disease (CD) is a chronic inflammatory condition that affects the gastrointestinal tract, particularly the ileum and colon. This disease is characterized by recurrent bouts of intestinal inflammation with subsequent bowel wall damage, including scarring (i.e., fibrosis) and abnormal smooth muscle proliferation. MR enterography, an MRI examination tailored to assess the small bowel, is a first-line diagnostic tool for diagnosing CD in children, characterization and monitoring of disease severity and extent, and assessment of disease-related complications. To date, such MRI evaluations have been mostly qualitative, which can adversely impact diagnostic performance and inter-radiologist agreement. Quantitative MRI methods have been shown to aid in the evaluation of a variety of medical conditions and have been increasingly investigated in children and adults with CD. In CD, such objective techniques have been used to assist with diagnosis, assess treatment response, and characterize bowel wall histologic abnormalities. In the current work, we will review quantitative MRI methods for detecting and measuring intestinal active inflammation (MRI-based scoring systems, T1 relaxation mapping, diffusion-weighted imaging, intra-voxel incoherent motion, mesenteric phase contrast), bowel wall damage (magnetization transfer), and motility (quantitative cine imaging) in small bowel CD, with an emphasis on the pediatric population.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes (T2D) or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as FIB-4) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise and discouraging alcohol consumption - as well as optimal management of comorbidities - including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for T2D or obesity, if indicated - is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.

Hepatic alterations are common aftereffects of heart failure (HF) and ventricular dysfunction. The prognostic value of liver injury markers derived from cardiac MRI studies in nonischemic dilated cardiomyopathy (DCM) patients is unclear.

Evaluate the prognostic performance of liver injury markers derived from cardiac MRI studies in DCM patients.

Prospective.

Three hundred fifty-six consecutive DCM patients diagnosed according to ESC guidelines (age 48.7 ± 14.2 years, males 72.6%).

Steady-state free precession, modified Look-Locker inversion recovery T1 mapping and phase sensitive inversion recovery late gadolinium enhancement (LGE) sequences at 3 T.

Clinical characteristics, conventional MRI parameters (ventricular volumes, function, mass), native myocardial and liver T1, liver extracellular volume (ECV), and myocardial LGE presence were assessed. Patients were followed up for a median duration of 48.3 months (interquartile range 42.0-69.9 months). Primary endpoints included HF death, sudden cardiac death, heart transplantation, and HF readmission; secondary endpoints included HF death, sudden cardiac death, and heart transplantation. Models were developed to predict endpoints and the incremental value of including liver parameters assessed.

Optimal cut-off value was determined using receiver operating characteristic curve and Youden method. Survival analysis was performed using Kaplan-Meier and Cox proportional hazard. Discriminative power of models was compared using net reclassification improvement and integrated discriminatory index. P value <0.05 was considered statistically significant.

47.2% patients reached primary endpoints; 25.8% patients reached secondary endpoints. Patients with elevated liver ECV (cut-off 34.4%) had significantly higher risk reaching primary and secondary endpoints. Cox regression showed liver ECV was an independent prognostic predictor, and showed independent prognostic value for primary endpoints and long-term HF readmission compared to conventional clinical and cardiac MRI parameters.

Liver ECV is an independent prognostic predictor and may serve as an innovative approach for risk stratification for DCM.

1 TECHNICAL EFFICACY: Stage 2.

Fibrosis is the aberrant process of connective tissue deposition from abnormal tissue repair in response to sustained tissue injury caused by hypoxia, infection, or physical damage. It can affect almost all organs in the body causing dysfunction and ultimate organ failure. Tissue fibrosis also plays a vital role in carcinogenesis and cancer progression. The early and accurate diagnosis of organ fibrosis along with adequate surveillance are helpful to implement early disease-modifying interventions, important to reduce mortality and improve quality of life. While extensive research has already been carried out on the topic, a thorough understanding of how this relationship reveals itself using modern imaging techniques has yet to be established. This work outlines the ways in which fibrosis shows up in abdominal organs and has listed the most relevant imaging technologies employed for its detection. New imaging technologies and developments are discussed along with their promising applications in the early detection of organ fibrosis.

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).

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.

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.

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.

Extracellular volume fraction (ECV), measured with contrast-enhanced magnetic resonance imaging (CE-MRI), has been utilized to study myocardial fibrosis, but its role in peripheral artery disease (PAD) remains unknown. We hypothesized that T1 mapping and ECV differ between PAD patients and matched controls.

A total of 37 individuals (18 PAD patients and 19 matched controls) underwent 3.0T CE-MRI. Skeletal calf muscle T1 mapping was performed before and after gadolinium contrast with a motion-corrected modified look-locker inversion recovery (MOLLI) pulse sequence. T1 values were calculated with a three-parameter Levenberg-Marquardt curve fitting algorithm. ECV and T1 maps were quantified in five calf muscle compartments (anterior [AM], lateral [LM], and deep posterior [DM] muscle groups; soleus [SM] and gastrocnemius [GM] muscles). Averaged peak blood pool T1 values were obtained from the posterior and anterior tibialis and peroneal arteries. T1 values and ECV are heterogeneous across calf muscle compartments. Native peak T1 values of the AM, LM, and DM were significantly higher in PAD patients compared to controls (all p < 0.028). ECVs of the AM and SM were significantly higher in PAD patients compared to controls (AM: 26.4% (21.2, 31.6) vs. 17.3% (10.2, 25.1), p = 0.046; SM: 22.7% (19.5, 27.8) vs. 13.8% (10.2, 19.1), p = 0.020).

Native peak T1 values across all five calf muscle compartments, and ECV fractions of the anterior muscle group and the soleus muscle were significantly elevated in PAD patients compared with matched controls. Non-invasive T1 mapping and ECV quantification may be of interest for the study of PAD.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes (T2D) or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as FIB-4) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise and discouraging alcohol consumption - as well as optimal management of comorbidities - including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for T2D or obesity, if indicated - is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.

Primary sclerosing cholangitis is a progressive inflammatory liver disease characterized by biliary and liver fibrosis. Vascular adhesion protein-1 (VAP-1) is important in the inflammatory process driving liver fibrosis. We evaluated the safety and efficacy of VAP-1 blockade with a monoclonal antibody (timolumab, BTT1023) in patients with primary sclerosing cholangitis.

BUTEO was a prospective, single-arm, open-label, multicenter, phase II trial, conducted in 6 centers in the United Kingdom. Patients with primary sclerosing cholangitis aged 18-75 years had an alkaline phosphatase value of >1.5 times the upper limit of normal. The dose-confirmatory stage aimed to confirm the safety of timolumab through the incidence of dose-limiting toxicity and sufficient trough levels of circulating antibody to block VAP-1 function. The primary outcome of the dose-expansion portion of the trial was patient's response to timolumab at day 99, as measured by a reduction in serum alkaline phosphatase by 25% or more from baseline to day 99.

Twenty-three patients were recruited: 7 into the initial dose-confirmatory stage and a further 16 into an expansion stage. Timolumab (8 mg/kg) was confirmed to be safe for the duration of administration with sufficient circulating levels. Only 2 of the 18 evaluable patients (11.1%) achieved a reduction in alkaline phosphatase levels of 25% or more, and both the proportion of circulating inflammatory cell populations and biomarkers of fibrosis remained unchanged from baseline.

The BUTEO trial confirmed 8 mg/kg timolumab had no short-term safety signals and resulted in sufficient circulating levels of VAP-1 blocking timolumab. However, the trial was stopped after an interim assessment due to a lack of efficacy as determined by no significant change in serum liver tests.

We established normal ranges for native T1 and T2 values in the human liver using a 1.5 T whole-body imager (General Electric) and we evaluated their variation across hepatic segments and their association with age and sex.

One-hundred healthy volunteers aged 20-70 years (50% females) underwent MRI. Modified Look-Locker inversion recovery and multi-echo fast-spin-echo sequences were used to measure hepatic native global and segmental T1 and T2 values, respectively.

T1 and T2 values exhibited good intra- and inter-observer reproducibility (coefficient of variation < 5%). T1 value over segment 4 was significantly lower than the T1 values over segments 2 and 3 (p < 0.0001). No significant regional T2 variability was detected. Segmental and global T1 values were not associated with age or sex. Global T2 values were independent from age but were significantly lower in males than in females. The lower and upper limits of normal for global T1 values were, respectively, 442 ms and 705 ms. The normal range for global T2 values was 35 ms-54 ms in males and 39 ms-54 ms in females.

Liver T1 and T2 mapping is feasible and reproducible and the provided normal ranges may help to establish diagnosis and progression of various liver diseases.

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease, with a worldwide prevalence of 25%. NAFLD is a spectrum that includes nonalcoholic fatty liver defined histologically by isolated hepatocytes steatosis without inflammation and nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of NAFLD and is associated with disease progression, development of cirrhosis, and increased rates of liver-specific and overall mortality. The differentiation between NAFLD and NASH as well as staging NASH are important yet challenging clinical problems. Liver biopsy is currently the standard for disease diagnosis and fibrosis staging. However, this procedure is invasive, costly, and cannot be used for longitudinal monitoring. Therefore, several noninvasive quantitative imaging biomarkers have been proposed that can estimate the severity of hepatic steatosis and fibrosis. Despite this, noninvasive diagnosis of NASH and accurate risk stratification remain unmet needs. In this work, the most relevant available imaging biomarkers are reviewed and their application in patients with NAFLD are discussed.

Accurate diagnosis and staging of liver fibrosis is crucial to the individualized management of patients with chronic liver disease. Liver biopsy remains the reference standard for the assessment of steatosis, necroinflammation, and fibrosis. However, over the past decade, there has been an exponential growth in noninvasive tests (NITs) designed to assess liver fibrosis and steatosis. These NITs range from serum biomarkers to imaging assessments of liver tissue stiffness. Current noninvasive methods overcome the limitations of non-specific laboratory markers, conventional imaging, and invasive procedures, and are now starting to be adopted. The Fibrosis-4 index, Enhanced Liver Fibrosis test, and elastography have gained the strongest clinical footholds for the diagnosis of advanced fibrosis. There remains significant interest in demonstrating superiority of any specific test or, alternatively, optimizing a sequential algorithm to provide the most accurate diagnosis of fibrosis staging. This article reviews currently available noninvasive methods for assessing liver fibrosis and steatosis.

Liver biopsy remains the gold standard for the histological assessment of the liver. With clear disadvantages and the rise in the incidences of liver disease, the role of neoadjuvant chemotherapy in colorectal liver metastasis (CRLM) and an explosion of surgical management options available, non-invasive serological and imaging markers of liver histopathology have never been more pertinent in order to assess liver health and stratify patients considered for surgical intervention. Liver MRI is a leading modality in the assessment of hepatic malignancy. Recent technological advancements in multiparametric MRI software such as the LiverMultiScanTM offers an attractive non-invasive assay of anatomy and histopathology in the pre-operative setting, especially in the context of CRLM. This narrative review examines the evidence for the LiverMultiScanTM in the assessment of hepatic fibrosis, steatosis/steatohepatitis, and potential applications for chemotherapy-associated hepatic changes. We postulate its future role and the hurdles it must surpass in order to be implemented in the pre-operative management of patients undergoing hepatic resection for colorectal liver metastasis. Such a role likely extends to other hepatic malignancies planned for resection.

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease worldwide. There are limited biomarkers that can detect progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The purpose of our study was to utilize CT texture analysis to distinguish steatosis from NASH.

16 patients with NAFLD (38% male, median (interquartile range): age 57 (48-64) years, BMI 37.5 (35.0-46.8) kg/m2) underwent liver biopsy and abdominal non-contrast CT. CT texture analysis was performed to quantify gray-level tissue summaries (e.g., entropy, kurtosis, skewness, and attenuation) using commercially available software (TexRad, Cambridge England). Logistic regression analyses were performed to quantify the association between steatosis/NASH status and CT texture. ROC curve analysis was performed to determine sensitivity, specificity, AUC, 95% CIs, and cutoff values of texture parameters to differentiate steatosis from NASH.

By histology, 6/16 (37%) of patients had simple steatosis and 10/16 (63%) had NASH. Patients with NASH had lower entropy (median, interquartile range (IQR): 4.3 (4.1, 4.8) vs. 5.0 (4.9, 5.2), P = 0.013) and lower mean value of positive pixels (MPP) (34.4 (21.8, 52.2) vs. 66.5 (57.0, 70.7), P = 0.009) than those with simple steatosis. Entropy values below 4.73 predict NASH with 100% (95%CI: 67-100%) specificity and 80% (50-100%) sensitivity, AUC: 0.88. MPP values below 54.0 predict NASH with 100% (67-100%) specificity and 100% (50-100%) sensitivity, AUC 0.90.

Our study provides preliminary evidence that CT texture analysis may serve as a novel imaging biomarker for disease activity in NAFLD and the discrimination of steatosis and NASH.

The spoiled gradient recalled echo (SPGR) sequence with variable flip angles (FAs) enables whole liverT 1 $$ {T}_1 $$ mapping at high spatial resolutions but is strongly affected byB 1 + $$ {B}_1^{+} $$ inhomogeneities. The aim of this work was to study how the precision of acquiredT 1 $$ {T}_1 $$ maps is affected by theT 1 $$ {T}_1 $$ andB 1 + $$ {B}_1^{+} $$ ranges observed in the liver at 3T, as well as how noise propagates from the acquired signals into the resultingT 1 $$ {T}_1 $$ map.

TheT 1 $$ {T}_1 $$ variance was estimated through the Fisher information matrix with a total noise variance including, for the first time, theB 1 + $$ {B}_1^{+} $$ map noise as well as contributions from the SPGR noise.

Simulations were used to find the optimal FAs for both theB 1 + $$ {B}_1^{+} $$ mapping andT 1 $$ {T}_1 $$ mapping. The simulations results were validated in 10 volunteers.

Four optimized SPGR FAs of 2°, 2°, 15°, and 15° (TR = 4.1 ms) andB 1 + $$ {B}_1^{+} $$ map FAs of 65° and 130° achieved aT 1 $$ {T}_1 $$ coefficient of variation of 6.2 ± 1.7% across 10 volunteers and validated our theoretical model. Four optimal FAs outperformed five uniformly spaced FAs, saving the patient one breath-hold. For the liverB 1 + $$ {B}_1^{+} $$ andT 1 $$ {T}_1 $$ parameter space at 3T, a higher return inT 1 $$ {T}_1 $$ precision was obtained by investing FAs in the SPGR acquisition rather than in theB 1 + $$ {B}_1^{+} $$ map.

A novel framework was developed and validated to calculate the SPGRT 1 $$ {T}_1 $$ variance. This framework efficiently identifies optimal FA values and determines the total number of SPGR andB 1 + $$ {B}_1^{+} $$ measurements needed to achieve a desiredT 1 $$ {T}_1 $$ precision.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have been linked to changes in amino acid (AA) levels. The objective of the current study was to examine the relationship between MRI parameters that reflect inflammation and fibrosis and plasma AA concentrations in NAFLD patients. Plasma AA levels of 97 NAFLD patients from the MAST4HEALTH study were quantified with liquid chromatography. Medical, anthropometric and lifestyle characteristics were collected and biochemical parameters, as well as inflammatory and oxidative stress biomarkers, were measured. In total, subjects with a higher MRI-proton density fat fraction (MRI-PDFF) exhibited higher plasma AA levels compared to subjects with lower PDFF. The concentrations of BCAAs (p-Value: 0.03), AAAs (p-Value: 0.039), L-valine (p-Value: 0.029), L-tyrosine (p-Value: 0.039) and L-isoleucine (p-Value: 0.032) were found to be significantly higher in the higher PDFF group compared to lower group. Plasma AA levels varied according to MRI-PDFF. Significant associations were also demonstrated between AAs and MRI-PDFF and MRI-cT1, showing the potential utility of circulating AAs as diagnostic markers of NAFLD.

Magnetic resonance imaging-based technologies are non-invasive diagnostic tests that can be used to assess non-alcoholic fatty liver disease.

The study objectives were to assess the diagnostic test accuracy, clinical impact and cost-effectiveness of two magnetic resonance imaging-based technologies (LiverMultiScan and magnetic resonance elastography) for patients with non-alcoholic fatty liver disease for whom advanced fibrosis or cirrhosis had not been diagnosed and who had indeterminate results from fibrosis testing, or for whom transient elastography or acoustic radiation force impulse was unsuitable, or who had discordant results from fibrosis testing.

The data sources searched were MEDLINE, MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Database of Controlled Trials, Database of Abstracts of Reviews of Effects and the Health Technology Assessment.

A systematic review was conducted using established methods. Diagnostic test accuracy estimates were calculated using bivariate models and a summary receiver operating characteristic curve was calculated using a hierarchical model. A simple decision-tree model was developed to generate cost-effectiveness results.

The diagnostic test accuracy review (13 studies) and the clinical impact review (11 studies) only included one study that provided evidence for patients who had indeterminate or discordant results from fibrosis testing. No studies of patients for whom transient elastography or acoustic radiation force impulse were unsuitable were identified. Depending on fibrosis level, relevant published LiverMultiScan diagnostic test accuracy results ranged from 50% to 88% (sensitivity) and from 42% to 75% (specificity). No magnetic resonance elastography diagnostic test accuracy data were available for the specific population of interest. Results from the clinical impact review suggested that acceptability of LiverMultiScan was generally positive. To explore how the decision to proceed to biopsy is influenced by magnetic resonance imaging-based technologies, the External Assessment Group presented cost-effectiveness analyses for LiverMultiScan plus biopsy versus biopsy only. Base-case incremental cost-effectiveness ratio per quality-adjusted life year gained results for seven of the eight diagnostic test strategies considered showed that LiverMultiScan plus biopsy was dominated by biopsy only; for the remaining strategy (Brunt grade ≥2), the incremental cost-effectiveness ratio per quality-adjusted life year gained was £1,266,511. Results from threshold and scenario analyses demonstrated that External Assessment Group base-case results were robust to plausible variations in the magnitude of key parameters.

Diagnostic test accuracy, clinical impact and cost-effectiveness data for magnetic resonance imaging-based technologies for the population that is the focus of this assessment were limited.

Magnetic resonance imaging-based technologies may be useful to identify patients who may benefit from additional testing in the form of liver biopsy and those for whom this additional testing may not be necessary. However, there is a paucity of diagnostic test accuracy and clinical impact data for patients who have indeterminate results from fibrosis testing, for whom transient elastography or acoustic radiation force impulse are unsuitable or who had discordant results from fibrosis testing. Given the External Assessment Group cost-effectiveness analyses assumptions, the use of LiverMultiScan and magnetic resonance elastography for assessing non-alcoholic fatty liver disease for patients with inconclusive results from previous fibrosis testing is unlikely to be a cost-effective use of National Health Service resources compared with liver biopsy only.

This study is registered as PROSPERO CRD42021286891.

Funding for this study was provided by the Evidence Synthesis Programme of the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 10. See the NIHR Journals Library website for further project information.

Liver resection is the only curative treatment for colorectal liver metastases (CLM). Resectability decision-making is therefore a key determinant of outcomes. Wide variation has been demonstrated in resectability decision-making, despite the existence of criteria. This paper summarises a study protocol to evaluate the potential added value of two novel assessment tools in assessing CLM technical resectability: the Hepatica preoperative MR scan (MR-based volumetry, Couinaud segmentation, liver tissue characteristics and operative planning tool) and the LiMAx test (hepatic functional capacity).

This study uses a systematic multistep approach, whereby three preparatory workstreams aid the design of the final international case-based scenario survey:Workstream 1: systematic literature review of published resectability criteria.Workstream 2: international hepatopancreatobiliary (HPB) interviews.Workstream 3: international HPB questionnaire.Workstream 4: international HPB case-based scenario survey.The primary outcome measures are change in resectability decision-making and change in planned operative strategy, resulting from the novel test results. Secondary outcome measures are variability in CLM resectability decision-making and opinions on the role for novel tools.

The study protocol has been approved by a National Health Service Research Ethics Committee and registered with the Health Research Authority. Dissemination will be via international and national conferences. Manuscripts will be published.

The CoNoR Study is registered with ClinicalTrials.gov (registration number NCT04270851). The systematic review is registered on the PROSPERO database (registration number CRD42019136748).

The LIVIFY trial investigated the safety, tolerability, and efficacy of vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH).

This double-blind phase IIa study was conducted in two parts. Patients were randomised (1:1:1:1) to receive placebo, vonafexor 100 mg twice daily (VONA-100BID), vonafexor 200 mg once daily (VONA-200QD), or 400 mg vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B. The primary efficacy endpoint was a reduction in liver fat content (LFC) by MRI-proton density fat fraction, while secondary endpoints included reduced corrected T1 values and liver enzymes, from baseline to Week 12.

One hundred and twenty patients were randomised (Part A, n = 24; Part B, n = 96). In Part B, there was a significant reduction in least-square mean (SE) absolute change in LFC from baseline to Week 12 for VONA-100QD (-6.3% [0.9]) and VONA-200QD (-5.4% [0.9]), vs. placebo (-2.3% [0.9], p = 0.002 and 0.012, respectively). A >30% relative LFC reduction was achieved by 50.0% and 39.3% of patients in the VONA-100QD and VONA-200QD arms, respectively, but only in 12.5% in the placebo arm. Reductions in body weight, liver enzymes, and corrected T1 were also observed with vonafexor. Creatinine-based glomerular filtration rate improved in the active arms but not the placebo arm. Mild to moderate generalised pruritus was reported in 6.3%, 9.7%, and 18.2% of participants in the placebo, VONA-100QD, and VONA-200QD arms, respectively.

In patients with suspected fibrotic NASH, vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit.

2018-003119-22.

NCT03812029.

Non-alcoholic steatohepatitis (NASH) has become a leading cause of chronic liver disease worldwide. Affected patients are also at higher risk of developing chronic kidney disease. There are no approved therapies and only few options to treat this population. The phase IIa LIVIFY trial results show that single daily administration of oral vonafexor, an FXR agonist, leads in the short term to a reduction in liver fat, liver enzymes, fibrosis biomarkers, body weight and abdominal circumference, and a possible improvement in kidney function, while possible mild moderate pruritus (a peripheral FXR class effect) and an LDL-cholesterol increase are manageable with lower doses and statins. These results support exploration in longer and larger trials, with the aim of addressing the unmet medical need in NASH.

Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), represent a growing worldwide epidemic and a high unmet medical need, as no licensed drugs have been approved thus far. Currently, histopathological assessment of liver biopsies is mandatory as a primary endpoint for conditional drug approval. This requirement represents one of the main challenges in the field, as there is substantial variability in this invasive histopathological assessment, which leads to dramatically high screen-failure rates in clinical trials. Over the past decades, several non-invasive tests have been developed to correlate with liver histology and, eventually, outcomes to assess disease severity and longitudinal changes non-invasively. However, further data are needed to ensure their endorsement by regulatory authorities as alternatives to histological endpoints in phase 3 trials. This Review describes the challenges of drug development in NAFLD-NASH trials and potential mitigating strategies to move the field forward.

The hepatic diseases are extremely common in clinical practice. The correct classification of liver fibrosis is extremely important, as it influences therapy and predicts disease outcomes. The purpose of this study is to compare the diagnostic performance of point-shear wave elastography (pSWE) and magnetic resonance elastography (MRE) in the hepatic fibrosis diagnostic. A meta-analysis was carried out based on articles published until October 2020. The articles are available at following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Scientific Electronic Library Online, LILACS, Scopus, and CINAHL. Diagnostic performances were analyzed per METAVIR F2, using 3.5kPa as target fibrosis. Assessment of the methodological quality of the incorporated papers by the QUADAS-2 tool for pSWE and MRE. A total 2,153 studies articles were evaluated and 44 studies, comprising 6,081 patients with individual data, were included in the meta-analysis: 28 studies for pSWE and 16 studies for MRE. The pooled sensitivity and specificity were 0.86 (95%CI 0.80-0.90) and 0.88 (95%CI 0.85-0.91), respectively, for pSWE, compared with 0.94 (95%CI 0.89-0.97) and 0.95 (95%CI 0.89-0.98) respectively, for MRE. The pooled SROC curve for pSWE shows in the area under the curve (AUC) of 0.93 (95%CI 0.90-0.95), whereas the AUC for MRE was 0.98 (95%CI 0.96-0.99). The diagnostic odds ratio for pSWE and MRE were 41 (95%CI 24-72) and 293 (95%CI 86-1000), respectively. There was statistically significant heterogeneity for pSWE sensitivity (I² = 85.26, P<0.001) and specificity (I² = 89.46, P<0.001). The heterogeneity for MRE also was significant for sensitivity (I² = 73.28, P<0.001) and specificity (I² = 87.24, P<0.001). Therefore, both pSWE and MRE are suitable modalities for assessing liver fibrosis. In addition, MRE is a more accurate imaging technique than pSWE and can be used as alternative to invasive biopsy.

Liver fibrosis is characterized by macromolecule depositions. Recently, a novel technology termed macromolecular proton fraction quantification based on spin-lock magnetic resonance imaging (MPF-SL) is reported to measure macromolecule levels.

MPF-SL can detect early-stage liver fibrosis by measuring macromolecule levels in the liver.

Retrospective.

Fifty-five participants, including 22 with no fibrosis (F0) and 33 with early-stage fibrosis (F1-2), were recruited.

3 T; two-dimensional (2D) MPF-SL turbo spin-echo sequence, 2D spin-lock T1rho turbo spin-echo sequence, and multi-slice 2D gradient echo sequence.

Macromolecular proton fraction (MPF), T1rho, liver iron concentration (LIC), and fat fraction (FF) biomarkers were quantified within regions of interest.

Group comparison of the biomarkers using Mann-Whitney U tests; correlation between the biomarkers assessed using Spearman's rank correlation coefficient and linear regression with goodness-of-fit; fibrosis stage differentiation using receiver operating characteristic curve (ROC) analysis. P-value < 0.05 was considered statistically significant.

Average T1rho was 41.76 ± 2.94 msec for F0 and 41.15 ± 3.73 msec for F1-2 (P = 0.60). T1rho showed nonsignificant correlation with either liver fibrosis (ρ = -0.07; P = 0.61) or FF (ρ = -0.14; P = 0.35) but indicated a negative correlation with LIC (ρ = -0.66). MPF was 4.73 ± 0.45% and 5.65 ± 0.81% for F0 and F1-2 participants, respectively. MPF showed a positive correlation with liver fibrosis (ρ = 0.59), and no significant correlations with LIC (ρ = 0.02; P = 0.89) or FF (ρ = 0.05; P = 0.72). The area under the ROC curve was 0.85 (95% confidence interval [CI] 0.75-0.95) and 0.55 (95% CI 0.39-0.71; P = 0.55) for MPF and T1rho to discriminate between F0 and F1-2 fibrosis, respectively.

MPF-SL has the potential to diagnose early-stage liver fibrosis and does not appear to be confounded by either LIC or FF.

3 TECHNICAL EFFICACY STAGE: 3.

Inflammation is the key driver of liver fibrosis progression in non-alcoholic fatty liver disease (NAFLD). Unfortunately, it is often challenging to assess inflammation in NAFLD due to its dynamic nature and poor correlation with liver biochemical markers. Liver histology keeps its role as the standard tool, yet it is well-known for substantial sampling, intraobserver, and interobserver variability. Serum proinflammatory cytokines and apoptotic markers, namely cytokeratin-18, are well-studied with reasonable accuracy, whereas serum metabolomics and lipidomics have been adopted in some commercially available diagnostic models. Ultrasound and computed tomography imaging techniques are attractive due to their wide availability; yet their accuracies may not be comparable with magnetic resonance imaging-based tools. Machine learning and deep learning models, be they supervised or unsupervised learning, are promising tools to identify various subtypes of NAFLD, including those with dominating liver inflammation, contributing to sustainable care pathways for NAFLD.