Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health problem. The secondary stage in MASLD is steatohepatitis (MASH), the co-existence of steatosis and inflammation, a leading cause of progression to fibrosis and mortality. MASH resolution alone improves survival. Currently, MASH diagnosis is via liver biopsy. This study sought to evaluate the accuracy of imaging-based tests for MASH diagnosis, which offer a non-invasive method of diagnosis.

Eight academic literature databases were searched and references of previous systematic reviews and included papers were checked for additional papers. Liver biopsy was used for reference standard.

We report on 69 imaging-based studies. There were 31 studies on MRI, 27 on ultrasound, five on CT, 13 on transient elastography, eight on controlled attenuation parameter (CAP) and two on scintigraphy. The pathological definition of MASH was inconsistent, making it difficult to compare studies. 55/69 studies (79.71%) were deemed high-risk of bias as they had no preset thresholds and no validation. The two largest groups of imaging papers were on MRI and ultrasound. AUROCs were up to 0.93 for MRE, 0.90 for MRI, 1.0 for magnetic resonance spectroscopy (MRS) and 0.94 for ultrasound-based studies.

Our study found that the most promising imaging tools are MRI techniques or ultrasound-based scores and confirmed there is potential to utilise these for MASH diagnosis. However, many publications are single studies without independent prospective validation. Without this, there is no clear imaging tool or score currently available that is reliably tested to diagnose MASH.

Magnetic resonance elastography (MRE) can quantify tissue biomechanics noninvasively, including pathological hepatic states like metabolic dysfunction-associated steatohepatitis.

To compare the performance of 2D/3D-MRE using the gravitational (GT) transducer concept with the current commercial acoustic (AC) solution utilizing a 2D-MRE approach. Additionally, quality index markers (QIs) were proposed to identify image pixels with sufficient quality for reliably estimating tissue biomechanics.

Prospective.

One hundred seventy participants with suspected or confirmed liver disease (median age, 57 years [interquartile range (IQR), 46-65]; 66 females), and 11 healthy volunteers (median age, 31 years [IQR, 27-34]; 5 females).

Participants were scanned twice at 1.5 T and 60 Hz vibration frequency: first, using AC-MRE (2D-MRE, spin-echo EPI sequence, 11 seconds breath-hold), and second, using GT-MRE (2D- and 3D-MRE, gradient-echo sequence, 14 seconds breath-hold).

Image analysis was performed by four independent radiologists and one biomedical engineer. Additionally, superimposed analytic plane shear waves of known wavelength and attenuation at fixed shear modulus were used to propose pertinent QIs.

Spearman's correlation coefficient (r) was applied to assess the correlation between modalities. Interreader reproducibility was evaluated using Bland-Altman bias and reproducibility coefficients. P-values <0.05 were considered statistically significant.

Liver stiffness quantified via GT-2D/3D correlated well with AC-2D (r ≥ 0.89 [95% CI: 0.85-0.92]) and histopathological grading (r ≥ 0.84 [95% CI: 0.72-0.91]), demonstrating excellent agreement in Bland-Altman plots and between readers (κ ≥ 0.86 [95% CI: 0.81-0.91]). However, GT-2D showed a bias in overestimating stiffness compared to GT-3D. Proposed QIs enabled the identification of pixels deviating beyond 10% from true stiffness based on a combination of total wave amplitude, temporal sinusoidal nonlinearity, and wave signal-to-noise ratio for GT-3D.

GT-MRE represents an alternative to AC-MRE for noninvasive liver tissue characterization. Both GT-2D and 3D approaches correlated strongly with the established commercial approach, offering advanced capabilities in abdominal imaging compared to AC-MRE.

1 TECHNICAL EFFICACY: Stage 2.

Tissue stiffness plays a crucial role in regulating morphogenesis. The ability to measure and monitor the dynamic progression of tissue stiffness is important for generating and testing mechanistic hypotheses. Methods to measure tissue properties in vivo have been emerging but present challenges with spatial and temporal resolution especially in 3D, by their reliance on highly specialized equipment, and/or due to their invasive nature. Here, we introduce light sheet elastography, a noninvasive method that couples low-frequency shear waves with light sheet fluorescence microscopy by adapting commercially available instruments. With this method, we achieved in toto stiffness mapping of organ-stage mouse and zebrafish embryos at cellular resolution. Versatility of the method enabled time-lapse stiffness mapping during tissue remodeling and of the beating embryonic heart. This method expands the spectrum of tools available to biologists and presents opportunities for uncovering the mechanical basis of morphogenesis.

Motivated by elastography that utilizes tissue mechanical properties as biomarkers for liver disease, with the eventual objective of quantitatively linking histopathology and bulk mechanical properties, we develop a micromechanical modeling approach to capture the effects of fat and collagen deposition in the liver. Specifically, we utilize computational homogenization to convert the microstructural changes in hepatic lobule to the effective viscoelastic modulus of the liver tissue, i.e. predict the bulk material properties by analyzing the deformation of repeating unit cell. The lipid and collagen deposition is simulated with the help of ad hoc algorithms informed by histological observations. Collagen deposition is directly included in the computational model, while composite material theory is used to convert fat content to the microscopic mechanical properties, which in turn is included in the computational model. The results illustrate the model's ability to capture the effect of both fat and collagen deposition on the viscoelastic moduli and represents a step towards linking histopathological changes in the liver to its bulk mechanical properties, which can eventually provide insights for accurate diagnosis with elastography.

Transient elastography (TE), shear wave elastography, and/or magnetic resonance elastography (MRE), each providing liver stiffness measurement (LSM), are the most studied imaging-based noninvasive liver disease assessment (NILDA) techniques. To support the American Association for the Study of Liver Diseases guidelines on NILDA, we summarized the evidence on the accuracy of these LSM methods to stage liver fibrosis (F).

A comprehensive search for studies assessing LSM by TE, shear wave elastography, or MRE for the identification of significant fibrosis (F2-4), advanced fibrosis (F3-4), or cirrhosis (F4), using histopathology as the standard of reference by liver disease etiology in adults or children from inception to April 2022 was performed. We excluded studies with <50 patients with a single disease entity and mixed liver disease etiologies (with the exception of HCV/HIV coinfection). Out of 9447 studies, 240 with 61,193 patients were included in this systematic review. In adults, sensitivities for the identification of F2-4 ranged from 51% to 95%, for F3-4 from 70% to 100%, and for F4 from 60% to 100% across all techniques/diseases, whereas specificities ranged from 36% to 100%, 74% to 100%, and 67% to 99%, respectively. The largest body of evidence available was for TE; MRE appeared to be the most accurate method. Imaging-based NILDA outperformed blood-based NILDA in most comparisons, particularly for the identification of F3-4/F4. In the pediatric population, imaging-based NILDA is likely as accurate as in adults.

LSM from TE, shear wave elastography, and MRE shows acceptable to outstanding accuracy for the detection of liver fibrosis across various liver disease etiologies. Accuracy increased from F2-4 to F3-4 and was the highest for F4. Further research is needed to better standardize the use of imaging-based NILDA, particularly in pediatric liver diseases.

Motivated by elastography that utilizes tissue mechanical properties as biomarkers for liver disease, with the eventual objective of quantitatively linking histopathology and bulk mechanical properties, we develop a micromechanical modeling approach to capture the effects of fat and collagen deposition in the liver. Specifically, we utilize computational homogenization to convert the microstructural changes in hepatic lobule to the effective viscoelastic modulus of the liver tissue, i.e., predict the bulk material properties by analyzing the deformation of repeating unit cell. The lipid and collagen deposition is simulated with the help of ad hoc algorithms informed by histological observations. Collagen deposition is directly included in the computational model, while composite material theory is used to convert fat content to the microscopic mechanical properties, which in turn is included in the computational model. The results illustrate the model's ability to capture the effect of both fat and collagen deposition on the viscoelastic moduli and represents a step towards linking histopathological changes in the liver to its bulk mechanical properties, which can eventually provide insights for accurate diagnosis with elastography.

Fast and accurate assessment of skin mechanics holds great promise in diagnosing various epidermal diseases, yet substantial challenges remain in developing simple and wearable strategies for continuous monitoring. Here, we present a design concept, named active near-infrared spectroscopy patch (ANIRP) for continuously mapping skin mechanics. ANIRP addresses these challenges by integrating near-infrared (NIR) sensing with mechanical actuators, enabling rapid measurement (<1 s) of Young's modulus, high spatial sensing density (~1 cm2), and high spatial sensitivity (<1 mm). Unlike conventional electromechanical sensors, NIR sensors precisely capture vibrational frequencies propagated from the actuators without needing ultraclose contact, enhancing wearing comfort. Demonstrated examples include ANIRPs for comprehensively moduli mapping of artificial tissues with varied mechanical properties emulating tumorous fibrosis. On-body validation of the ANIRP across skin locations confirms its practical utility for clinical monitoring of epidermal mechanics, promising considerable advancements in real-time, noninvasive skin diagnostics and continuous health monitoring.

Quantitative MRI and ultrasound biomarkers of liver fibrosis have become important tools in the diagnosis and clinical management of children with chronic liver disease (CLD). In particular, MR elastography is now routinely performed in clinical practice to evaluate the liver for fibrosis. Ultrasound shear-wave elastography has also become widely performed for this purpose, especially in young children. These noninvasive methods are increasingly used to replace liver biopsy for the diagnosis, quantitative staging, and treatment monitoring of patients with CLD. Although ultrasound has the advantages of portability and lower equipment cost than MRI, available evidence indicates that MRI may have greater reliability and accuracy in liver fibrosis evaluation. In this AJR Expert Panel Narrative Review, we describe how, why, and when to use MRI- and ultrasound-based elastography methods for liver fibrosis assessment in children. Practical approaches are discussed for adapting and optimizing these methods in children, with consideration of clinical indications, patient preparation, equipment requirements, and acquisition technique, as well as pitfalls and confounding factors. Guidance is provided for interpretation and reporting, and representative case examples are presented.

We aimed to explore the extent to which individuals previously diagnosed with nonalcoholic fatty liver disease (NAFLD) meet the criteria fulfilled with the new nomenclature, metabolic dysfunction-associated steatotic liver disease (MASLD), within an Asian primary clinic cohort. Additionally, we assessed the reliability of the diagnostic performance of FIB-4 and NAFLD fibrosis score (NFS) for MASLD within the primary clinic cohort.

This retrospective cross-sectional study included participants who underwent magnetic resonance elastography and abdominal ultrasonography during their health checkups at nationwide health promotion centers (n = 6740).

The prevalence rates of NAFLD and MASLD diagnosed based on ultrasonography results were 36.7% and 38.0%, respectively. Notably, 96.8% of patients in the NAFLD cohort fulfilled the new criteria for MASLD. A small proportion of patients with NAFLD (n = 80, 3.2%) did not meet the MASLD criteria. Additionally, 168 patients (6.6%) were newly added to the MASLD group. The areas under the receiver operating characteristic curves for diagnosing advanced hepatic fibrosis for FIB-4 (0.824 in NAFLD vs. 0.818 in MASLD, p = 0.891) and NFS (0.803 in NAFLD vs. 0.781 in MASLD, p = 0.618) were comparable between the MASLD and NAFLD groups. Furthermore, the sensitivity, specificity, positive predictive value, and negative predictive value of FIB-4 and NFS for advanced fibrosis in MASLD were also comparable to those in NAFLD.

Most patients (96.8%) previously diagnosed with NAFLD fulfilled the new criteria for MASLD in an Asian primary clinic cohort. Diagnostic performance of FIB-4 in the MASLD cohort demonstrated satisfactory results.

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is increasing, affecting over one-third of the global population and contributing to significant morbidity and mortality. Diagnosing MAFLD, especially with advanced fibrosis, remains challenging due to the limitations of liver biopsy, the current gold standard. Non-invasive tests are crucial for early detection and management. Among these, the fibrosis-4 index (Fib-4) is widely recommended as a first-line test for screening for liver fibrosis. Advanced imaging techniques, including ultrasound-based elastography and magnetic resonance elastography, offer high accuracy but are limited by cost and availability. Combining biomarkers, such as in the enhanced liver fibrosis score and FibroScan-AST score, enhances diagnostic precision and is recommended to further stratify patients who are considered to be intermediate or high risk from the Fib-4 score. We believe that the future lies in the combined use of biomarkers to improve diagnostic accuracy.

Cirrhosis represents a significant global health challenge, characterized by high morbidity and mortality rates that severely impact human health. Timely and precise prognostic assessments of liver cirrhosis are crucial for improving patient outcomes and reducing mortality rates as they enable physicians to identify high-risk patients and implement early interventions. This paper features a thorough literature review on the prognostic assessment of liver cirrhosis, aiming to summarize and delineate the present status and constraints associated with the application of traditional prognostic tools in clinical settings. Among these tools, the Child-Pugh and Model for End-Stage Liver Disease (MELD) scoring systems are predominantly utilized. However, their accuracy varies significantly. These systems are generally suitable for broad assessments but lack condition-specific applicability and fail to capture the risks associated with dynamic changes in patient conditions. Future research in this field is poised for deep exploration into the integration of artificial intelligence (AI) with routine clinical and multi-omics data in patients with cirrhosis. The goal is to transition from static, unimodal assessment models to dynamic, multimodal frameworks. Such advancements will not only improve the precision of prognostic tools but also facilitate personalized medicine approaches, potentially revolutionizing clinical outcomes.

Since 1980, the cumulative effort of scientists and health-care stakeholders has advanced the prerequisites to address metabolic dysfunction-associated steatotic liver disease (MASLD), a prevalent chronic non-communicable liver disease. This effort has led to, among others, the approval of the first drug specific for metabolic dysfunction-associated steatohepatitis (MASH; formerly known as nonalcoholic steatohepatitis). Despite substantial progress, MASLD is still a leading cause of advanced chronic liver disease, including primary liver cancer. This Perspective contextualizes the nomenclature change from nonalcoholic fatty liver disease to MASLD and proposes important considerations to accelerate further progress in the field, optimize patient-centric multidisciplinary care pathways, advance pharmacological, behavioural and diagnostic research, and address health disparities. Key regulatory and other steps necessary to optimize the approval and access to upcoming additional pharmacological therapeutic agents for MASH are also outlined. We conclude by calling for increased education and awareness, enhanced health system preparedness, and concerted action by policy-makers to further the public health and policy agenda to achieve at least parity with other non-communicable diseases and to aid in growing the community of practice to reduce the human and economic burden and end the public health threat of MASLD and MASH by 2030.

Opinions differ regarding vibration-controlled transient elastography and magnetic resonance elastography (VCTE/MRE) cut-offs for diagnosing advanced fibrosis (AF) in patients with non-alcoholic fatty liver disease (NAFLD). We investigated the diagnostic performance and optimal cut-off values of VCTE and MRE for diagnosing AF.

Literature databases, including Medline, EMBASE, Cochrane Library, and KoreaMed, were used to identify relevant studies published up to June 13, 2023. We selected studies evaluating VCTE and MRE regarding the degree of liver fibrosis using liver biopsy as the reference. The sensitivity, specificity, and area under receiver operating characteristics curves (AUCs) of the pooled data for VCTE and MRE for each fibrosis stage and optimal cut-offs for AF were investigated.

A total of 19,199 patients from 63 studies using VCTE showed diagnostic AUC of 0.83 (95% confidence interval: 0.80-0.86), 0.83 (0.80-0.86), 0.87 (0.84-0.90), and 0.94 (0.91-0.96) for ≥F1, ≥F2, ≥F3, and F4 stages, respectively. Similarly, 1,484 patients from 14 studies using MRE showed diagnostic AUC of 0.89 (0.86-0.92), 0.92 (0.89-0.94), 0.89 (0.86-0.92), and 0.94 (0.91-0.96) for ≥F1, ≥F2, ≥F3, and F4 stages, respectively. The diagnostic AUC for AF using VCTE was highest at 0.90 with a cut-off of 7.1-7.9 kPa, and that of MRE was highest at 0.94 with a cut-off of 3.62-3.8 kPa.

VCTE (7.1-7.9 kPa) and MRE (3.62-3.8 kPa) with the suggested cut-offs showed favorable accuracy for diagnosing AF in patients with NAFLD. This result will serve as a basis for clinical guidelines for non-invasive tests and differential diagnosis of AF.

Risk of disease progression and clinical outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with fibrosis stage and presence of "at-risk metabolic dysfunction-associated steatohepatitis (MASH)." Although liver biopsy is considered the gold standard to diagnose MASH and stage of fibrosis, biopsy is infrequently performed in clinical practice and has associated sampling error, lack of interrater reliability, and risk for procedural complications. Noninvasive tests (NITs) are routinely used in clinical practice for risk stratification of patients with MASLD. Several NITs are being developed for detecting "at-risk MASH" and cirrhosis. Clinical care guidelines apply NITs to identify patients needing subspecialty referral. With recently approved Food and Drug Administration treatment for MASH and additional emerging pharmacotherapy, NITs will identify patients who will most benefit from treatment, monitor treatment response, and assess risk for long-term clinical outcomes. In this review, we examine the performance of NITs to detect "at-risk MASH," fibrosis stage, response to treatment, and risk of clinical outcomes in MASLD and MASH.

The predictors of progression from steatosis to more advanced stages of metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear. We evaluated the association between the quantity of hepatic steatosis and longitudinal changes in liver stiffness measurements (LSMs) using magnetic resonance elastography (MRE) in patients with MASLD.

We retrospectively analysed patients with MASLD who underwent at least two serial MRE and magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) examinations at least 1 year apart. Fine-Gray competitive proportional hazard regression was used to identify LSM progression and regression factors.

A total of 471 patients were enrolled. Factors linked to LSM progression were steatosis grade 3 (MRI-PDFF ≥17.1%, adjusted hazard ratio [aHR] 2.597; 95% confidence interval [CI] 1.483-4.547) and albumin-bilirubin grade 2 or 3 (aHR 2.790; 95% CI 1.284-6.091), while the only factor linked to LSM regression was % decrease rate of MRI-PDFF ≥5% (aHR 2.781; 95% CI 1.584-4.883). Steatosis grade 3 correlated with a higher incidence rate of LSM progression than steatosis grade 1 (MRI-PDFF <11.3%) in patients with LSM stage 0 (<2.5 kilopascal [kPa]), and a % annual decrease rate of MRI-PDFF ≥5% correlated with a higher incidence rate of LSM regression than that of MRI-PDFF >-5% and <5% in patients with LSM stage 1 or 2-4 (≥2.5 kPa).

Severe hepatic steatosis was linked to significant LSM progression in patients with MASLD and low LSM (<2.5 kPa).

There are limited data on the prevalence and treatment of at-risk metabolic dysfunction-associated steatohepatitis (MASH) among patients with type 2 diabetes (T2DM) in the United States.

To estimate the prevalence of at-risk MASH in a prospectively recruited cohort of adults with T2DM using new nomenclature endorsed by multiple societies.

This prospective study enrolled adults aged ≥50 with T2DM from primary care and endocrinology clinics in southern California from 2016 to 2023. Metabolic dysfunction-associated steatotic liver disease (MASLD) was defined by an magnetic resonance imaging proton density fat fraction ≥5% and at least one metabolic risk factor without any other chronic liver disease or secondary cause for hepatic steatosis.

We included 530 adult patients with T2DM. The mean (±SD) age and body mass index (BMI) were 64.4 (±8.1) years and 31.5 (±6.1) kg/m2, respectively. Among patients with T2DM, the prevalence of MASLD, at-risk MASH and cirrhosis was 69.6%, 13.6% and 6.8%, respectively. Among patients with co-existing T2DM and obesity, the prevalence of MASLD, at-risk MASH and cirrhosis was 77.8%, 15.9% and 9.0%, respectively, and was higher than in participants without obesity (p < 0.0001, 0.0543 and 0.0128, respectively).

Among adults aged ≥50 years with T2DM, the prevalence of MASLD, at-risk MASH and cirrhosis is high, posing a significant risk for liver-related morbidity and mortality. Approximately 14% of patients with T2DM may be candidates for pharmacologic therapies specific to MASH-related fibrosis.

A diagnosis of cirrhosis initiates a shift in the management of chronic liver disease and affects the diagnostic workflow and treatment decision of primary liver cancer. Liver biopsy remains the gold standard for cirrhosis diagnosis, but it is invasive and susceptible to sampling bias and observer variability. Various qualitative and quantitative imaging biomarkers based on ultrasound, CT and MRI have been proposed for noninvasive diagnosis of cirrhosis. Qualitative imaging features are easy to apply but have moderate diagnostic sensitivity. Elastography techniques allow quantitative assessment of liver stiffness and are highly accurate for cirrhosis diagnosis. Ultrasound elastography are widely used in clinical practice, while MR elastography has narrower availability. Although not applicable in clinical practice yet, other quantitative imaging features, including liver surface nodularity, linear and volumetric measurement, extracellular volume fraction, liver enhancement on hepatobiliary phase, and parameters derived from diffusion-weighted imaging, can provide additional information of liver morphology, perfusion, and function, thus may increase diagnosis performance. The introduction of radiomics and deep learning has further improved diagnostic accuracy while reducing subjectivity. Several imaging features may also help to assess liver function and outcomes in patients with cirrhosis. In this review, we summarize the qualitative and quantitative imaging biomarkers for noninvasive cirrhosis diagnosis, and the assessment of liver function and outcomes, and discuss the challenges and future directions in this field.

Recently, the American Gastroenterological Association and the American Association for the Study of Liver Diseases developed clinical pathways to evaluate populations at high risk for NAFLD. We assessed the diagnostic performance of the new guidance in a well-phenotyped cohort of patients with Type 2 diabetes mellitus (T2DM).

This prospective study enrolled patients age ≥50 years with T2DM. Participants underwent a standardized clinical research visit with MRI and ultrasound-based assessment of liver fat and stiffness and Enhanced Liver Fibrosis (ELF) testing. Of 417 participants (36% men) with T2DM with FIB-4 and MRE data, the prevalence of NAFLD was 64% and 12% had advanced fibrosis (MRE≥3.63 kPa). Applying the American Gastroenterological Association pathway of FIB-4 and vibration-controlled transient elastography, the false negative rate was 3.3% and 18% would qualify for specialty referral. Applying the FIB-4 + ELF American Association for the Study of Liver Diseases pathway, the false negative rate was 4.5%, but 50% would qualify for specialty referral. Applying higher ELF cut points improved the pathway, yielding a similar false negative rate of 4.9% but decreased specialty referral to 27%.

Validation of the American Gastroenterological Association clinical pathway in a prospectively recruited cohort with T2DM revealed a low false negative rate and avoided specialty referral in a large percentage of patients. The American Association for the Study of Liver Diseases pathway with FIB-4 + ELF resulted in a high rate of specialty referral, which improved with the utilization of higher ELF cut points and may serve as an alternative for primary care and endocrinology clinics without access to vibration-controlled transient elastography.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent condition with a broad spectrum defined by liver biopsy. This gold standard method evaluates three features: steatosis, activity (ballooning and lobular inflammation), and fibrosis, attributing them to certain grades or stages using a semiquantitative scoring system. However, liver biopsy is subject to numerous restrictions, creating an unmet need for a reliable and reproducible method for MASLD assessment, grading, and staging. Noninvasive imaging modalities, such as magnetic resonance imaging (MRI), offer the potential to assess quantitative liver parameters. This review aims to provide an overview of the available MRI techniques for the three criteria evaluated individually by liver histology. Here, we discuss the possibility of combining multiple MRI parameters to replace liver biopsy with a holistic, multiparametric MRI protocol. In conclusion, the development and implementation of such an approach could significantly improve the diagnosis and management of MASLD, reducing the need for invasive procedures and paving the way for more personalized treatment strategies.

Non-alcoholic fatty liver disease (NAFLD) is a major public health issue worldwide. It is the most common liver disease in Western countries, andits global prevalence is estimated to be up to 35%. However, its diagnosis may be elusive, because liver biopsy is relatively rarely performed and usually only in advanced stages of the disease. Therefore, several non-invasive scores may be applied to more easily diagnose and monitor NAFLD. In this review, we discuss the various biomarkers and imaging scores that could be useful in diagnosing and managing NAFLD. Despite the fact that general measures, such as abstinence from alcohol and modulation of other cardiovascular disease risk factors, should be applied, the mainstay of prevention and management is weight loss. Bariatric surgery may be suggested as a means to confront NAFLD. In addition, pharmacological treatment with GLP-1 analogues or the GIP agonist tirzepatide may be advisable. In this review, we focus on the utility of GLP-1 analogues and GIP agonists in lowering body weight, their pharmaceutical potential, and their safety profile, as already evidenced inanimal and human studies. We also elaborate on other options, such as the use of vitamin E, probiotics, especially next-generation probiotics, and prebiotics in this context. Finally, we explore future perspectives regarding the administration of GLP-1 analogues, GIP agonists, and probiotics/prebiotics as a means to prevent and combat NAFLD. The newest drugs pegozafermin and resmetiron, which seem to be very promising, arealso discussed.

The development and validation of non-invasive fibrosis tests (NITs) has changed clinical practice in Hepatology over the last 15 years. Metabolic associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most prevalent liver disease in western countries, with up to a third of the unselected adult population affected. In this article, we review the use of NITs in the diagnosis and staging of MASLD. We discuss their use in the diagnosis of steatosis, steatohepatitis and fibrosis and critically evaluate recently published data. These NITs include a variety of approaches, such as serum markers like FIB-4, pro-C3 and ELF, imaging techniques like Fibroscan® and MRE, and combined scores like Agile 3+ and Agile 4, offering a range of options for healthcare providers. Furthermore, these non-invasive tests also serve as valuable prognostic tools, allowing for better risk assessment and improved patient management, particularly in predicting liver-related events and overall mortality.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease throughout the world. Hepatocellular carcinoma (HCC) and liver cirrhosis can result from nonalcoholic steatohepatitis (NASH), the severe stage of NAFLD progression. By some estimates, NAFLD affects almost one-third of the world's population, which is completely new and serious public health issue. Unfortunately, NAFLD is diagnosed by exclusion, and the gold standard for identifying NAFLD/NASH and reliably measuring liver fibrosis remains liver biopsy, which is an invasive, costly, time-consuming procedure and involves variable inter-observer diagnosis. With the progress of omics and imaging techniques, numerous non-invasive serological assays have been generated and developed. On the basis of these developments, non-invasive biomarkers and imaging techniques have been combined to increase diagnostic accuracy. This review provides information for the diagnosis and assessment of NAFLD/NASH in clinical practice going forward and may assist the clinician in making an early and accurate diagnosis and in proposing a cost-effective patient surveillance. We discuss newly identified and validated non-invasive diagnostic methods from biopsy-confirmed NAFLD patient studies and their implementation in clinical practice, encompassing NAFLD/NASH diagnosis and differentiation, fibrosis assessment, and disease progression monitoring. A series of tests, including 20-carboxy arachidonic acid (20-COOH AA) and 13,14-dihydro-15-keto prostaglandin D2 (dhk PGD2), were found to be potentially the most accurate non-invasive tests for diagnosing NAFLD. Additionally, the Three-dimensional magnetic resonance imaging (3D-MRE), combination of the FM-fibro index and Liver stiffness measurement (FM-fibro LSM index) and the machine learning algorithm (MLA) tests are more accurate than other tests in assessing liver fibrosis. However, it is essential to use bigger cohort studies to corroborate a number of non-invasive diagnostic tests with extremely elevated diagnostic values.

Chronic liver disease is highly prevalent and often leads to fibrosis or cirrhosis and complications such as liver failure and hepatocellular carcinoma. The diagnosis and staging of liver fibrosis is crucial to determine management and mitigate complications. Liver biopsy for histologic assessment has limitations such as sampling bias and high interreader variability that reduce precision, which is particularly challenging in longitudinal monitoring. MR elastography (MRE) is considered the most accurate noninvasive technique for diagnosing and staging liver fibrosis. In MRE, low-frequency vibrations are applied to the abdomen, and the propagation of shear waves through the liver is analyzed to measure liver stiffness, a biomarker for the detection and staging of liver fibrosis. As MRE has become more widely used in clinical care and research, different contexts of use have emerged. This review focuses on the latest developments in the use of MRE for the assessment of liver fibrosis; provides guidance for image acquisition and interpretation; summarizes diagnostic performance, along with thresholds for diagnosis and staging of liver fibrosis; discusses current and emerging clinical applications; and describes the latest technical developments.

Nonalcoholic fatty liver disease (NAFLD) is increasing worldwide and is a growing cause of liver cirrhosis and cancer. The performance of the magnetic resonance elastography (MRE) visco-elastic parameters in diagnosing progressive forms of NAFLD, including nonalcoholic steatohepatitis (NASH) and substantial fibrosis (F ≥ 2), needs to be clarified.

To assess the value of three-dimensional MRE visco-elastic parameters as markers of NASH and substantial fibrosis in mice with NAFLD.

Prospective.

Two mouse models of NAFLD were induced by feeding with high fat diet or high fat, choline-deficient, amino acid-defined diet.

7T/multi-slice multi-echo spin-echo MRE at 400 Hz with motion encoding in the three spatial directions.

Hepatic storage and loss moduli were calculated. Histological analysis was based on the NASH Clinical Research Network criteria.

Mann-Whitney, Kruskal-Wallis tests, Spearman rank correlations and multiple regressions were used. Diagnostic performance was assessed with areas under the receiver operating characteristic curves (AUCs). P value <0.05 was considered significant.

Among the 59 mice with NAFLD, 21 had NASH and 20 had substantial fibrosis (including 8 mice without and 12 mice with NASH). The storage and loss moduli had similar moderate accuracy for diagnosing NASH with AUCs of 0.67 and 0.66, respectively. For diagnosing substantial fibrosis, the AUC of the storage modulus was 0.73 and the AUC of the loss modulus was 0.81, indicating good diagnostic performance. Using Spearman correlations, histological fibrosis, inflammation and steatosis, but not ballooning, were significantly correlated with the visco-elastic parameters. Using multiple regression, fibrosis was the only histological feature independently associated with the visco-elastic parameters.

MRE in mice with NAFLD suggests that the storage and loss moduli have good diagnostic performance for detecting progressive NAFLD defined as substantial fibrosis rather than NASH.

1 TECHNICAL EFFICACY STAGE: 2.

(1) Assess the diagnostic performance of liver 3D magnetic resonance elastography (MRE) parameters (including stiffness, storage/loss modulus and damping ratio) compared to liver stiffness measured with 2D MRE for noninvasive detection of advanced liver fibrosis (F3-F4) and cirrhosis (F4) in patients with chronic liver disease. (2) Assess the value of serum markers (FIB-4) in detecting advanced liver fibrosis and cirrhosis in the same patients.

This was a single center, prospective IRB-approved cross-sectional study that included 49 patients (M/F: 23/26, mean age 50.8 y) with chronic liver disease and concomitant liver biopsy. MRE was acquired at 1.5T using a spin echo-EPI sequence. The following parameters were measured: liver stiffness using 2D MRE (LS-2D) and 3D MRE parameters (LS-3D, liver storage, loss modulus and damping ratio). The Mann-Whitney U test, ROC curve analysis, Spearman correlation and logistic regression were performed to evaluate diagnostic performance of MRE parameters and FIB-4.

LS-2D and LS-3D had similar diagnostic performance for diagnosis of F3-F4, with AUCs of 0.87 and 0.88, sensitivity of 0.71 and 0.81, specificity of 0.89 for both. For diagnosis of F4, LS-2D and LS-3D had similar performance with AUCs of 0.81 for both, sensitivity of 0.75 and 0.83, and specificity of 0.84 and 0.73, respectively. Additional 3D parameters (storage modulus, loss modulus, damping ratio) had variable performance, with AUC range of 0.59-0.78 for F3-F4; and 0.52-0.70 for F4. FIB-4 had lower diagnostic performance, with AUCs of 0.66 for F3-F4, and 0.68 for F4.

Our study shows no added value of 3D MRE compared to 2D MRE for detection of advanced fibrosis and cirrhosis, while FIB-4 had lower diagnostic performance.

Viral hepatitis was previously the most common cause of chronic liver disease. However, in recent years, nonalcoholic fatty liver disease (NAFLD) cases have been increasing, especially in developed countries. NAFLD is histologically characterized by fat, fibrosis, and inflammation in the liver, eventually leading to cirrhosis and hepatocellular carcinoma. Although biopsy is the gold standard for the assessment of the liver parenchyma, quantitative evaluation methods, such as ultrasound, CT, and MRI, have been reported to have good diagnostic performances. The quantification of liver fat, fibrosis, and inflammation is expected to be clinically useful in terms of the prognosis, early intervention, and treatment response for the management of NAFLD. The aim of this review was to discuss the basics and prospects of MRI-based tissue quantifications of the liver, mainly focusing on proton density fat fraction for the quantification of fat deposition, MR elastography for the quantification of fibrosis, and multifrequency MR elastography for the evaluation of inflammation.

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.

We conducted an individual patient data meta-analysis to establish stiffness cut-off values for magnetic resonance elastography (MRE) in staging liver fibrosis and to assess potential confounding factors.

A systematic review of the literature identified studies reporting MRE data in patients with NAFLD. Data were obtained from the corresponding authors. The pooled diagnostic cut-off value for the various fibrosis stages was determined in a two-stage meta-analysis. Multilevel modelling methods were used to analyse potential confounding factors influencing the diagnostic accuracy of MRE in staging liver fibrosis.

Eight independent cohorts comprising 798 patients were included in the meta-analysis. The area under the receiver operating characteristic curve (AUROC) for MRE in detecting significant fibrosis was 0.92 (sensitivity, 79%; specificity, 89%). For advanced fibrosis, the AUROC was 0.92 (sensitivity, 87%; specificity, 88%). For cirrhosis, the AUROC was 0.94 (sensitivity, 88%, specificity, 89%). Cut-offs were defined to explore concordance between MRE and histopathology: ≥F2, 3.14 kPa (pretest probability, 39.4%); ≥F3, 3.53 kPa (pretest probability, 24.1%); and F4, 4.45 kPa (pretest probability, 8.7%). In generalized linear mixed model analysis, histological steatohepatitis with higher inflammatory activity (odds ratio 2.448, 95% CI 1.180-5.079, p <0.05) and high gamma-glutamyl transferase (GGT) concentration (>120U/L) (odds ratio 3.388, 95% CI 1.577-7.278, p <0.01] were significantly associated with elevated liver stiffness, and thus affecting accuracy in staging early fibrosis (F0-F1). Steatosis, as measured by magnetic resonance imaging proton density fat fraction, and body mass index(BMI) were not confounders.

MRE has excellent diagnostic performance for significant, advanced fibrosis and cirrhosis in patients with NAFLD. Elevated inflammatory activity and GGT level may lead to overestimation of early liver fibrosis, but anthropometric measures such as BMI or the degree of steatosis do not.

This individual patient data meta-analysis of eight international cohorts, including 798 patients, demonstrated that MRE achieves excellent diagnostic accuracy for significant, advanced fibrosis and cirrhosis in patients with NAFLD. Cut-off values (significant fibrosis, 3.14 kPa; advanced fibrosis, 3.53 kPa; and cirrhosis, 4.45 kPa) were established. Elevated inflammatory activity and gamma-glutamyltransferase level may affect the diagnostic accuracy of MRE, leading to overestimation of liver fibrosis in early stages. We observed no impact of diabetes, obesity, or any other metabolic disorder on the diagnostic accuracy of MRE.

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are independent risk factors for cardiovascular disease (CVD).

To examine the clinical utility of liver fat quantification for determining CVD risk among a well-phenotyped cohort of patients with T2DM.

This was a cross-sectional analysis of a prospective cohort of adults aged ≥50 with T2DM. Liver fat was quantified with magnetic resonance imaging proton-density-fat-fraction (MRI-PDFF), an advanced imaging-based biomarker. Patients were stratified into a higher liver fat group (MRI-PDFF ≥ 14.6%), and a lower liver fat group (MRI-PDFF < 14.6%). The co-primary outcomes were CVD risk determined by Framingham and Atherosclerotic Cardiovascular Disease (ASCVD) risk scores. High CVD risk was defined by risk scores ≥20%.

Of the 391 adults (66% female) in this study, the mean (±SD) age was 64 (±8) years and BMI 30.8 (±5.2) kg/m2 , respectively. In multivariable analysis, adjusted for age, gender, race, and BMI, patients in the higher liver fat group had higher CVD risk [OR = 4.04 (95% CI: 2.07-7.88, p < 0.0001)] and ASCVD risk score [OR = 2.85 (95% CI: 1.19-6.83, p = 0.018)], respectively.

Higher liver fat content increases CVD risk independently of age, gender, ethnicity and BMI. These findings raise the question whether liver fat quantification should be incorporated into risk calculators to further stratify those with higher CVD risk.

The non-invasive identification of liver fibrosis related to Non-Alcoholic Fatty Liver Disease is crucial for risk-stratification of patients. Currently, the reference standard to stage hepatic fibrosis relies on liver biopsy, but multiple approaches are developed to allow for non-invasive diagnosis and risk stratification. Non-invasive tests, including blood-based scores and vibration-controlled transient elastography, have been widely validated and represent a good surrogate for risk stratification according to recent European and American guidelines.

Novel approaches are based on 'liquid' biomarkers of liver fibrogenesis, including collagen-derived markers (PRO-C3 or PRO-C6), or 'multi-omics' technologies (e.g. proteomic-based molecules or miRNA testing), bearing the advantage of tailoring the intrahepatic disease activity. Alternative approaches are based on 'dry' biomarkers, including magnetic resonance-based tools (including proton density fat fraction, magnetic resonance elastography, or corrected T1), which reach similar accuracy of liver histology and will potentially help identify the best candidates for pharmacological treatment of fibrosing non-alcoholic steatohepatitis.

In the near future, the sequential use of non-invasive tests, as well as the complimentary use of liquid and dry biomarkers according to the clinical need (diagnosis, risk stratification, and prognosis, or treatment response) will guide and improve the management of this liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent form of chronic liver disease that poses challenges in diagnosis and risk stratification. Non-alcoholic steatohepatitis (NASH), the more progressive form of NAFLD, is particularly challenging to diagnose in the absence of histology. Liver biopsy is infrequently performed due to its invasive nature, potential for sampling error, and lack of inter-rater reliability. Non-invasive tests that can accurately identify patients with at-risk NASH (ie, individuals with biopsy-proven NASH with NAFLD activity score [NAS] ≥4 and fibrosis stage ≥2) are key tools to identify candidates for pharmacologic therapy in registrational trials for the treatment of NASH-related fibrosis. With emerging pharmacotherapy, non-invasive tests are required to track treatment response. Lastly, there is an unmet need for non-invasive tests to assess risk for clinical outcomes including progression to cirrhosis, hepatic decompensation, liver-related mortality, and overall mortality. In this Review we examine advances in non-invasive tests to diagnose and monitor NAFLD and NASH.

Most noninvasive tests (NITs) for hepatic fibrosis are designed for middle-aged patients with chronic liver disease. We compared the diagnostic performance of major NITs (aspartate aminotransferase-to-platelet ratio index [APRI], Fibrosis-4 index, and nonalcoholic fatty liver disease fibrosis score) for a community-based cohort.

This cross-sectional study analyzed 8775 participants who underwent magnetic resonance elastography at community health check-up centers. Advanced hepatic fibrosis (≥F3) was defined by magnetic resonance elastography thresholds of 3.6 kPa. The diagnostic performance of 3 NITs was evaluated according to the etiology of liver disease, sex, metabolic syndrome, obesity, and increased aminotransferase levels in 4 age groups.

The APRI generally showed the best area under the receiver operating characteristic curve in patients aged 45 years or younger, and it was statistically significant in patients with chronic viral hepatitis and alcoholic fatty liver disease (P < .043). The best APRI cut-off value for detecting advanced hepatic fibrosis was 0.4, with a sensitivity and specificity of 75.8% and 73.5%, respectively, in the community-based cohort. The APRI showed balanced sensitivity and specificity across all age groups, whereas the other metrics showed low sensitivity in those aged <45 and low specificity in those >65 years.

The APRI showed better sensitivity and negative predictive value than the Fibrosis-4 index and the nonalcoholic fatty liver disease fibrosis score in community-based populations with mixed etiology, and, thus, can be performed as the primary test in young adults (age, ≤45 y).

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a major public health problem worldwide. Liver fibrosis is closely correlated with liver functional reserve and the risk of HCC development. Meanwhile, malignant tumors generally have high cellularity compared to benign tumors, which results in increased stiffness. Magnetic resonance elastography (MRE) has emerged as a new non-invasive technique for assessing tissue stiffness with excellent diagnostic accuracy, not only for assessing liver fibrosis but also for measuring tumor stiffness. Recent studies provide new evidence that MRE may play an important role in the management of patients with HCC and show several novel clinical applications, such as predicting the development of HCC, differentiating between benign/malignant liver lesions (FLL) and HCC pathological grades, assessing treatment response, and predicting recurrence after treatment, although some findings are controversial. Therefore, we conducted this review to summarize these novel applications of MRE in HCC patients and also discuss their limitations and future advancement.

There are limited prospective data on patients with type 2 diabetes mellitus (T2DM) specifically enrolled and systematically assessed for advanced fibrosis or cirrhosis due to non-alcoholic fatty liver disease (NAFLD). Therefore, we aimed to evaluate the prevalence of advanced fibrosis and cirrhosis in a prospectively recruited cohort of adults with T2DM.

This prospective study enrolled adults aged ≥50 years with T2DM, recruited from primary care or endocrinology clinics. Participants underwent a standardized clinical research visit with MRI-proton density fat fraction (MRI-PDFF), magnetic resonance elastography (MRE), vibration-controlled transient elastography (VCTE) and controlled-attenuation parameter. NAFLD was defined as MRI-PDFF ≥5% after exclusion of other liver diseases. Advanced fibrosis and cirrhosis were defined by established liver stiffness cut-off points on MRE or VCTE if MRE was not available.

Of 524 patients screened, 501 adults (63% female) with T2DM met eligibility. The mean age and BMI were 64.6 (±8.1) years and 31.4 (±5.9) kg/m2, respectively. The prevalence of NAFLD, advanced fibrosis and cirrhosis was 65%, 14% and 6%, respectively. In multivariable adjusted models, adjusted for age and sex, obesity and insulin use were associated with increased odds of advanced fibrosis (odds ratio 2.50; 95% CI 1.38-4.54; p = 0.003 and odds ratio 2.71; 95% CI 1.33-5.50; p = 0.006, respectively). Among 29 patients with cirrhosis, two were found to have hepatocellular carcinoma and one patient had gallbladder adenocarcinoma.

Utilizing a uniquely well-phenotyped prospective cohort of patients aged ≥50 years with T2DM, we found that the prevalence of advanced fibrosis was 14% and that of cirrhosis was 6%. These data underscore the high risk of advanced fibrosis/cirrhosis in adults aged ≥50 years with T2DM.

Non-alcoholic fatty liver disease (NAFLD) is common in patients with type 2 diabetes (T2DM), however, there are limited prospective data characterizing the prevalence of advanced fibrosis and cirrhosis using the most accurate non-invasive biomarkers of liver fat and fibrosis. We show that 14% of older adults with T2DM have advanced fibrosis and 6% have cirrhosis, which places them at risk for liver failure and liver cancer. Accurate prevalence rates and comparative analysis regarding the diagnostic accuracy of non-invasive tests in this population will guide the optimal screening strategy and future cost-effectiveness analyses. These results will inform future Hepatology and Endocrinology practice guidelines regarding NAFLD screening programs in older adults with T2DM.

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent worldwide and becoming a major cause of liver disease-related morbidity and mortality. The presence of liver fibrosis in patients with NAFLD is closely related to prognosis, including the development of hepatocellular carcinoma and other complications of cirrhosis. Therefore, assessment of the presence of significant or advanced liver fibrosis is crucial. Although liver biopsy has been considered the "gold standard" method for evaluating the degree of liver fibrosis, it is not suitable for extensive use in all patients with NAFLD owing to its invasiveness and high cost. Therefore, noninvasive biochemical and imaging biomarkers have been developed to overcome the limitations of liver biopsy. Imaging biomarkers for the stratification of liver fibrosis have been evaluated in patients with NAFLD using different imaging techniques, such as transient elastography, shear wave elastography, and magnetic resonance elastography. Furthermore, artificial intelligence and deep learning methods are increasingly being applied to improve the diagnostic accuracy of imaging techniques and overcome the pitfalls of existing imaging biomarkers. In this review, we describe the usefulness and future prospects of noninvasive imaging biomarkers that have been studied and used to evaluate the degree of liver fibrosis in patients with NAFLD.