Screening for advanced fibrosis (AF) resulting from metabolic dysfunction-associated steatotic liver disease (MASLD) is recommended in diabetology. This study aimed to compare the performance of noninvasive tests (NITs) with that of two-step algorithms for detecting patients at high risk of AF requiring referral to hepatologists.

We conducted a planned interim analysis of a prospective multicenter study including participants with type 2 diabetes and/or obesity and MASLD with comprehensive liver assessment comprising blood-based NITs, vibration-controlled transient elastography (VCTE), and two-dimensional shear-wave elastography (2D-SWE). AF risk stratification was determined by a composite criterion of liver biopsy, magnetic resonance elastography, or VCTE ≥12 kPa depending on availability.

Of 654 patients (87% with type 2 diabetes, 56% male, 74% with obesity), 17.6% had an intermediate/high risk of AF, and 9.3% had a high risk of AF. The area under the empirical receiver operating characteristic curves of NITs for detection of high risk of AF were as follows: fibrosis-4 index (FIB-4) score, 0.78 (95% CI 0.72-0.84); FibroMeter, 0.74 (0.66-0.83); FibroTest, 0.78 (0.72-0.85); Enhanced Liver Fibrosis (ELF) test, 0.82 (0.76-0.87); and SWE, 0.84 (0.78-0.89). Algorithms with FIB-4 score/VCTE showed good diagnostic performance for referral of patients at intermediate/high risk of AF to specialized care in hepatology. An alternative FIB-4 score/ELF test strategy showed a high negative predictive value (NPV; 88-89%) and a lower positive predictive value (PPV; 39-46%) at a threshold of 9.8. The FIB-4 score/2D-SWE strategy had an NPV of 91% and a PPV of 58-62%. The age-adapted FIB-4 score threshold resulted in lower NPVs and PPVs in all algorithms.

The FIB-4 score/VCTE algorithm showed excellent diagnostic performance, demonstrating its applicability for routine screening in diabetology. The ELF test using an adapted low threshold at 9.8 may be used as an alternative to VCTE.

Nonalcoholic fatty liver disease (NAFLD), now known by the name of metabolic dysfunction-associated fatty liver disease (MAFLD), with increased global incidence, has been recognized as a significant metabolic disorder. NAFLD includes a spectrum liver disease from hepatocellular fat accumulation (isolated steatosis) to an advanced form of liver injury known as nonalcoholic steatohepatitis (NASH), which refers to distinct histologic features, including hepatocellular steatosis and injury, necroinflammation, and eventually fibrosis. Nonobese or lean individuals associated with metabolic dysregulation usually demonstrated diverse risk factors compared to obese MAFLD. The presence of normal range body mass index (BMI) and excess visceral adiposity with increased cardiometabolic and renal comorbidities, along with sarcopenia, has been evidenced to be associated with lean MASH. Genetic predispositions accompanying lifestyle and environmental factors contribute to disease initiation and progression. The genetic influence in pathophysiology indicated the significant contributions of the following genes: PNPLA3, TM6SF2, APOB, LIPA, MBOAT7, and HSD17B13, and the impact of their disease-specific variants in the development of obesity-independent MASH. The epigenetic modifications exhibited differential DNA methylation patterns in the genes involved in lipid metabolism, particularly hypomethylation of PEMT. Diet-induced and genetic animal models of lean MASH, including Slc: Wistar/ST rats, PPAR-α, PTEN, and MAT1A knockout mice models, are indicated to be pivotal in the exploration of disease progression and observing the effect of therapeutic interventions. This comprehensive review comprises the molecular and genetic pathophysiology, molecular diagnostics, and therapeutic aspects of lean MASH to enunciate a diagnostic approach that combines detailed clinical phenotyping regarding genomic analysis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is often regarded in society as a disease caused by personal lifestyle and dietary choices. Healthcare providers who have empathy and are able to explain the disease trajectory can better engage with people with MASLD and actively work with them to improve their metabolic health on a sustainable basis. Non-invasive tests can assist in this process, but healthcare providers must ensure they explain their advantages and limitations. Discussing and setting lifestyle goals are priorities before initiating specific pharmacological treatment, since living a healthy lifestyle will remain the backbone of the multimodal management of MASLD. In this review, we discuss challenges and opportunities to actively engage with people living with MASLD in a multimodal treatment framework as a healthcare provider.

Objective: The objective of this study was to calculate the epidemiological impact of metabolic dysfunction associated with fatty liver disease (MAFLD) and hepatic fibrosis in primary care (PC). Secondarily, we assessed the correlation between serological markers (FIB-4, ELF test), abdominal ultrasound, and transient elastography in the early detection of MAFLD. Methods: An observational prospective study was designed to determine the prevalence of MAFLD and to assess the correlation between complementary tests. Patients were recruited from five health centres. Eligible participants were adults aged between 18 and 70 years with at least one metabolic risk factor, including being overweight (BMI 25-29.9 kg/m2) or obese (BMI > 30 kg/m2), or diagnosed with type 2 diabetes mellitus (T2DM), dyslipidemia, or metabolic syndrome. The prevalence of MAFLD was calculated. Correlations between diagnostic tests were evaluated using Pearson's correlation coefficient. Results: A total of 98 patients was included. Using CAP (controlled attenuation parameter) measurements, the prevalence of MAFLD was found to be 67.7%, and the prevalence of hepatic fibrosis was 6.5%. The correlation between conventional ultrasound and CAP from FibroScan® for the diagnosis of MAFLD was low and not statistically significant (0.160 [95% CI: -0.100; 0.400], p = 0.226). In contrast, the diagnosis of hepatic fibrosis using FibroScan® in PC showed a high correlation with diagnoses performed in gastroenterology department (0.942 [95% CI: 0.844; 0.979], p < 0.001). The correlation with biochemical markers was low and not statistically significant for both FIB-4 (0.125 [95% CI: -0.129; 0.363], p = 0.334) and the ELF test (0.159 [95% CI: -0.111; 0.407], p = 0.246). Conclusions: Two out of three patients with metabolic risk factors were diagnosed with MAFLD, while hepatic fibrosis diagnoses were uncommon. These results reinforce the validity of using FibroScan® in PC.

Therapeutic trials in metabolic dysfunction-associated steatohepatitis (MASH) are hampered by a high 70-80% screen failure rate mostly because of the absence of fibrotic MASH on baseline liver biopsies, underscoring the need for better selection of candidates. We compared the performance of eight non-invasive tests, designed or not for the diagnosis of fibrotic MASH.

A total of 1,005 patients with histologically proven MASLD were included in five tertiary care centers. Three non-invasive tests developed for fibrotic MASH were evaluated: the simple blood test Fibrotic NASH Index (FNI), the specialized blood test MACK-3, and the elastography-based test FAST. Five non-invasive tests recommended for advanced fibrosis were evaluated as well: the simple blood test FIB-4, the specialized blood tests FibroTest and Enhanced Liver Fibrosis test (ELF™), and the elastography-based tests FibroScan and Agile3+. Fibrotic MASH was defined as MASH with MASLD activity score ≥4 and fibrosis score F ≥2.

Among simple blood tests (n = 1,005), FNI had a significantly higher area under the receiver operating characteristic (AUROC) for fibrotic MASH than FIB-4 (0.709 [0.677-0.741] vs. 0.662 [0.628-0.695], p = 0.019). Among elastography-based tests (n = 817), FAST had a significantly higher AUROC (0.774 [0.743-0.806]) than FibroScan (0.728 [0.694-0.763], p = 0.013) and Agile3+ (0.708 [0.672-0.744], p = 0.004). Among specialized blood tests (n = 545), MACK-3 had a significantly higher AUROC (0.772 [0.734-0.811]) than FibroTest (0.615 [0.568-0.663], p <0.001) and ELF (0.700 [0.656-0.744], p = 0.028). Sequential combination (FAST then Agile3+; MACK-3 then ELF) identified a subset including one-third of patients in whom the false-positive rate was only 30%.

Sequential combinations using first-line tests designed for fibrotic MASH improves the identification of candidates for MASH therapeutic trials.

Drug development in metabolic dysfunction-associated steatohepatitis (MASH) is hampered by a high screen failure rate, one of the main reasons being the absence of MASH and significant fibrosis (fibrotic MASH) on the baseline liver biopsy, a key inclusion criterion in MASH therapeutic trials. Non-invasive tests represent an attractive opportunity to better select candidates for these trials, but most of them have been developed for advanced fibrosis and the new tests designed for the diagnosis of fibrotic MASH remain poorly validated. In this work, we demonstrate that the tests specifically designed for fibrotic MASH are more accurate for this diagnostic target than the tests currently recommended and initially developed for advanced fibrosis. We propose sequential combinations that will facilitate the identification of patients with fibrotic MASH in need of treatment, and their inclusion in MASH therapeutic trials.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading causes of chronic liver disease globally. Based on the 2023 definition, MASLD is characterized by the presence of metabolic dysfunction and limited alcohol consumption (<140 grams/week for women, <210 grams/week for men). Given the significant burden of MASLD in Latin America, this guidance was developed by the Latin American Association for the Study of the Liver (ALEH) Working Group to address key aspects of its clinical assessment and therapeutic strategies. In Latin America, ultrasonography is recommended as the initial screening tool for hepatic steatosis due to its accessibility, while Fibrosis-4 (FIB-4) is preferred for fibrosis risk stratification, with further evaluation using more specific techniques (i.e., vibration-controlled transient elastography or Enhanced Liver Fibrosis [ELF] test). A Mediterranean diet is advised for all MASLD patients, with a target of 7-10% weight loss for those with excess weight. Complete alcohol abstinence is recommended for patients with significant fibrosis, and smoking cessation is encouraged regardless of fibrosis stage. Pharmacological options should be tailored based on the presence of steatohepatitis, liver fibrosis, excess weight, and diabetes, including resmetirom, incretin-based therapies, pioglitazone, and sodium-glucose cotransporter-2 inhibitors. Bariatric surgery may be considered for MASLD patients with obesity unresponsive to lifestyle and medical interventions. Hepatocellular carcinoma screening is advised for all cirrhotic patients, with consideration given to those with advanced fibrosis based on individual risk. Finally, routine cardiovascular risk assessment and proper diabetes prevention and management remain crucial for all patients with MASLD.

The enhanced liver fibrosis (ELF) test has good discrimination performance in detecting advanced liver fibrosis. The chronic liver disease (CLivD) risk score based on clinical data accurately predicts risk for future severe liver disease. Considering the ELF test as a surrogate marker for liver fibrosis, we analyzed predictors of elevated ELF (eELF) and its change.

The study cohort consisted of Finnish general population-based health surveys Health2000 and a follow-up study 10 years later Health2011 with 6084 and 2937 individuals, respectively with phenotype and ELF data. eELF was defined as ELF ≥ 9.8, and clinically relevant fibrosis progression as an ELF change ≥0.6. CLivD risk score was calculated at baseline. Analyses were age-adjusted.

Obesity measures and diabetes predicted eELF at baseline. Only waist-hip ratio (WHR) could predict clinically relevant fibrosis progression over the follow-up consistently among men and women (OR 1.35 and 1.41, respectively). High-risk alcohol use was a significant risk factor for eELF only among men (OR 1.72, p = 0.049), and it did not predict fibrosis progression in either sex. Although elevated transaminases were associated with eELF, in most individuals with eELF they were within reference limits. Increased CLivD scores correlated with baseline and the change of ELF values over the 10-year follow-up independent of baseline ELF (p < 0.001).

Liver fibrosis progression is difficult to predict based on single risk factors or liver enzymes. ELF had limited value to predict fibrosis progression. The CLivD score, based on multiple risk factors, predicted both occurrence of baseline eELF and its progression over a 10-year follow-up.

Antifibrotic trials rely on conventional pathology despite recognized limitations. We compared single-fiber digital image analysis with conventional pathology to quantify the antifibrotic effect of Aramchol, a stearoyl-CoA desaturase 1 inhibitor in development for metabolic dysfunction-associated steatohepatitis.

Fifty-one patients with metabolic dysfunction-associated steatohepatitis enrolled in the open-label part of the ARMOR trial received Aramchol 300 mg BID and had paired pre-post treatment liver biopsies scored by consensus among 3 hepatopathologists, and separately assessed by a digital image analysis platform (PharmaNest) that generates a continuous phenotypic Fibrosis Composite Severity (Ph-FCS) score. Fibrosis improvement was defined as: ≥1 NASH Clinical Research Network (NASH-CRN) stage reduction; "improved" by ranked pair assessment; reduction in Ph-FCS ("any" for ≥0.3 absolute reduction and "substantial" for ≥25% relative reduction). Fibrosis improved in 31% of patients (NASH-CRN), 51% (ranked pair assessment), 74.5% (any Ph-FCS reduction), and 41% (substantial Ph-FCS reduction). Most patients with stable fibrosis by NASH-CRN or ranked pair assessment had a Ph-FCS reduction (a third with substantial reduction). Fibrosis improvement increased with treatment duration: 25% for <48 weeks versus 39% for ≥48 weeks by NASH-CRN; 43% versus 61% by ranked pair assessment, mean Ph-FCS reduction -0.54 (SD: 1.22) versus -1.72 (SD: 1.02); Ph-FCS reduction (any in 54% vs. 100%, substantial in 21% vs. 65%). The antifibrotic effect of Aramchol was corroborated by reductions in liver stiffness, Pro-C3, and enhanced liver fibrosis. Changes in Ph-FCS were positively correlated with changes in liver stiffness.

Continuous fibrosis scores generated in antifibrotic trials by digital image analysis quantify antifibrotic effects with greater sensitivity and a larger dynamic range than conventional pathology.

Non-invasive tests (NITs) identifying high-risk MASLD in primary care is suggested but, these strategies cost-effectiveness remain uncertain in the United Kingdom (UK).

A cost-utility/budget impact model was developed for cost-effectiveness evaluation of two screening strategies (1) FIB-4 followed by Enhanced Liver Fibrosis (ELF) (FIB-4/ELF); (2) FIB-4 followed by Transient Elastography (FIB-4/TE) compared to standard of care (SoC). A cohort of primary care MASLD patients with an advanced fibrosis prevalence of 4.20 % was simulated. A decision tree classified patients as true positives, false positives, true negatives, or false negatives based on NIT diagnostic accuracy, followed by a 3-year Markov model to estimate costs and quality-adjusted life years (QALYs). The model included 11 health states: MASLD, fibrosis stages (F0-F3), cirrhosis, decompensated cirrhosis, liver transplant, and death. Costs came from the National Tariff, National Schedule of Costs and Personal Social Services Research Unit.

SoC had a false diagnosis rate of 36.26 %, while FIB-4 with ELF or TE reduced false positive rates to 23.20 % and 20.91 %, respectively. Compared to 112,807 unnecessary hepatology referrals under SoC, FIB-4/ELF or FIB-4/TE reduced unnecessary referrals by 38,031 (33.71 %) and 45,767 (40.57 %), respectively. Both strategies demonstrated cost-effectiveness relative to SoC with total cost per patient of GBP 983.37 for FIB-4/TE, GBP 993.15 for FIB-4/ELF compared to SoC, GBP 1,014.15.

Sequential NIT screening strategies, combining FIB-4 with ELF or TE, are cost-saving, reduce unnecessary hepatology referrals, and offer an efficient (improve outcomes and reduce healthcare costs) approach for managing high-risk MASLD in UK primary care.

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.

The performance of non-invasive liver tests (NITs) is known to vary across settings and subgroups. We systematically evaluated whether the performance of three NITs in detecting advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) varies with age, sex, body mass index (BMI), type 2 diabetes mellitus (T2DM) status or liver enzymes.

Data from 586 adult LITMUS Metacohort participants with histologically characterised MASLD were included. The diagnostic performance of the Fibrosis-4 Index (FIB-4), enhanced liver fibrosis (ELF) and vibration-controlled transient elastography liver stiffness measurement (VCTE LSM) was evaluated. Performance was expressed as the area under the receiver operating characteristics curve (AUC). Thresholds for detecting advanced fibrosis (≥F3) were calculated for each NIT for fixed (high) sensitivity, specificity and predictive values.

Differences in AUC between all subgroups were small and statistically not significant, indicating comparable performance in detecting ≥F3, irrespective of these clinical factors. However, different thresholds were needed to achieve the same level of accuracy with each test. For example, for a fixed sensitivity and specificity, the thresholds for all three NITs were higher in patients with T2DM. Effects for sex, age and liver enzymes were less pronounced.

Performance of the selected NITs in detecting advanced liver fibrosis does not vary substantially with clinical characteristics. However, different thresholds have to be selected to achieve the same sensitivity, specificity and predictive values in the respective subgroups. Large prospective studies are called for to study NIT accuracy considering multiple patient characteristics.

Biopsy is the gold standard method for diagnosing liver fibrosis. FibroScan is a non-invasive method of diagnosing liver fibrosis, but it still faces some limitations. This study aimed to establish a nomogram model and identify patients at high risk of advanced liver fibrosis associated with hepatitis B infection.

Data were collected from 375 patients with hepatitis B who underwent liver biopsy. Patients were divided randomly into the training (n = 263) and validation sets (n = 112). Their demographic and clinical characteristics were analyzed using the least absolute shrinkage and selection operator regression (LASSO). A nomogram model was established to predict the fibrosis stage, and its performance was assessed using the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA) and was compared with other recognized models.

In total, 209 patients with non-advanced fibrosis (S0-1) and 166 patients with advanced fibrosis (S ≥ 2) were included. Hyaluronic acid (HA), laminin, total cholesterol (TC), platelet, and age were entered into the nomogram model based on the LASSO analysis. The nomogram model for predicting advanced fibrosis exhibited a relatively high AUC in the training set. Compared with FIB4 and APRI, the nomogram model showed a better agreement between the actual status and predicted status based on the calibration curve. The nomogram model showed an AUC similar to FibroScan in the validation cohort, and showed high clinical net benefits in the training and validation sets.

Our nomogram model can help identify patients with hepatitis B and advanced liver fibrosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease and is projected to become the leading indication for liver transplant (LT) in the US. Understanding its clinical burden can help to identify opportunities for prevention and treatment.

To project the burden of MASLD in US adults from 2020 to 2050.

This decision analytical modeling study used an agent-based state transition model that simulates the natural history of MASLD progression among adults 18 years of age or older. Primary data sources for model inputs were the published literature.

Natural history of MASLD.

Cases of MASLD, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, hepatocellular carcinoma (HCC), LT, and liver-related death.

The model simulated 2 821 624 individuals (mean age. 35.8 years; 50.9% female). The model predicted a steady increase in the prevalence of MASLD from 33.7% (86.3 million people) in 2020 to 41.4% (121.9 million people) by 2050. Cases of MASH would increase from 14.9 million (5.8% of US adults) in 2020 to 23.2 million (7.9% of US adults) by 2050. The number of cases of MASH and clinically significant fibrosis (ie, F≥F2, centrilobular and periportal fibrosis or more severe disease) were estimated to increase from 6.7 million to 11.7 million. By 2046 to 2050, MASLD would cause 22 440 new cases of HCC and 6720 new cases of LT per year compared with 11 483 new cases of HCC and 1717 new cases of LT in 2020 to 2025. Liver-related mortality was estimated to increase from 30 500 deaths (1.0% of all-cause deaths in adults) in 2020 to 95 300 deaths (2.4%) in 2050.

In this decision analytical modeling study, the model forecast a substantial increase in clinical burden of MASLD over the next 3 decades in the absence of effective treatments. These results suggest that health systems should plan for large increases in the number of HCC cases and in the need for LT.

Obesity and associated insulin resistance induce a chronic metaboinflammatory state that lead to injury and dysfunction of multiple organs resulting in a cluster of noncommunicable diseases such as type 2 diabetes mellitus, hypertension, cardiovascular disease, chronic kidney disease, and metabolic dysfunction-associated steatotic liver disease (MASLD). Metabolic dysfunction-associated steatohepatitis (MASH) is a histologically active form of MASLD and characterized by greater injury and inflammation and progresses to cirrhosis with greater certainty than steatosis alone. The progression to cirrhosis is characterized by increasing fibrosis. The goal of treatment of MASLD/MASH was to improve the metaboinflammatory state i.e., the root cause of the liver disease and to prevent fibrosis progression to cirrhosis whereas in those who already have cirrhosis need additional care to prevent portal hypertension-related outcomes. Fibrosis regression is thus a key objective of treatment. The recent approval of resmetirom for MASH with fibrosis and the use of glucagon-like peptide-1 receptor agonists for obesity and type 2 diabetes has increased awareness of these NCDs and resulted in the growing demand for liver assessment and care in obese individuals. Patients with MASLD also have multiple metabolic comorbidities which represent competing threats to life, and the care of the patient requires both assessment of the totality of the risk and a more holistic approach integrating the care of all of the threats to life. Here, we provide a pragmatic and easily implementable risk-based approach to the evaluation and management of MASLD.

Various noninvasive tests can be used to identify high-risk groups of patients with metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD). In this study, we compared the diagnostic performance of serum type 4 collagen 7S (COL4-7S) and the Enhanced Liver Fibrosis (ELF) score for detecting fibrosis in patients with MASLD.

Among 1368 patients with MASLD who underwent liver biopsy, 794 with values for both serum COL4-7S and the ELF score were enrolled in this multicenter study. The diagnostic performance of COL4-7S and ELF for detecting fibrosis stage ≥2, fibrosis stage ≥3, and at-risk metabolic dysfunction-associated steatohepatitis were evaluated using ROC curve, continuous net reclassification improvement, and integrated discrimination improvement analyses.

Both COL4-7S and ELF scores increased significantly with increasing fibrosis. The AUROC for each outcome was higher for COL4-7S than ELF, but not significantly. The diagnostic performance for detecting fibrosis stage ≥2 was significantly better for COL4-7S than for the ELF score (s net reclassification improvement=16.7%, p=0.018; integrated discrimination improvement=3.9%, p<0.01). In patients without diabetes, the diagnostic performance for each outcome did not differ significantly between COL4-7S and ELF score, but in patients with diabetes, the diagnostic performance for fibrosis stage ≥2 was higher for COL4-7S than for the ELF score (AUROC=0.817 vs. 0.773, p=0.04; s net reclassification improvement=32.7%, p<0.01; integrated discrimination improvement=5.6%, p<0.01).

The diagnostic performance of serum COL4-7S (a single marker) for identifying more advanced disease in patients with MASLD was at least equivalent to that of the ELF score (a combined marker).

Non-alcoholic fatty liver disease is a globally prevalent disorder that can rapidly progress if not detected early. Currently, no accepted markers exist for early diagnosis and prognosis of NAFLD. This review describes derangement in major metabolic pathways of lipid, carbohydrate, and amino acids in NAFLD. It suggests that measuring levels of thrombospondin, TyG index, asymmetric dimethylarginine, LAL-A, GLP-1, FGF-21, and GSG index are potential markers for early diagnosis of NAFLD. A single marker may not indicate early NAFLD, and further large-scale studies on correlating levels of Thrombospondin-2, triglyceride-glucose index, and FGF-21 with NAFLD are warranted.

Liver fibrosis, a critical predictor of the prognosis of metabolic dysfunction-associated steatotic liver disease (MASLD), is traditionally diagnosed via biopsy. Nevertheless, non-invasive alternatives, such as serum biomarkers, vibration-controlled transient elastography, and magnetic resonance elastography, have become prominent because of the limitations of biopsies. Serum biomarkers, such as fibrosis-4 index and NFS Score, are also used widely, offering reliable diagnostic performance for advanced fibrosis. Vibration-controlled transient elastography and shear wave elastography provide further non-invasive evaluations with high diagnostic accuracy, particularly for advanced fibrosis, but the results may be affected by factors such as obesity. Magnetic resonance elastography, with superior diagnostic accuracy and operator independence, is a promising method, but its high cost and limited availability restrict its widespread use. Emerging algorithms, such as NIS4, FAST, or MAST score, have strong potential in identifying high-risk metabolic dysfunction-associated steatohepatitis patients. The integration of multiple non-invasive methods can optimize diagnostic accuracy, reducing the need for invasive biopsies while identifying patients at risk of liver-related complications. Further research is needed to refine these diagnostic tools and improve accessibility.

Chronic liver disease is a significant public health issue worldwide, with the degree of liver fibrosis and its progression significantly influencing the treatment and prognosis. A liver biopsy is the standard diagnostic method, but it is invasive and presents various issues. Therefore, numerous non-invasive diagnostic methods have been developed. Serum markers are categorized into indirect markers, which reflect liver damage, inflammation, or functional changes, and direct markers, which measure the components released into the bloodstream during fibrosis. In addition, various kinds of formulas that combined direct/indirect markers and demographic variables were developed and validated with encouraging outcomes. Nevertheless, despite their convenience, serum indicators require cautious interpretation because they are affected by a number of factors. More research will be needed to determine if the clinical course of chronic liver disease under a disease-specific treatment could be monitored appropriately using serological markers.

Provide a concise update on metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), as well as a practical approach to screening and initial evaluation.

Nomenclature changes have placed a greater focus on cardiometabolic risk factors in the definition of MASLD. Screening for MASLD is by stepwise noninvasive serum and imaging tests which can identify patients at risk for advanced fibrosis and liver-related complications. MASLD has been increasing in prevalence and disease burden but is underrecognized in primary care and endocrinology clinics. Multiple society guidelines, synthesized here, provide a framework for the initial approach in the diagnosis and evaluation of MASLD. Recent advances in pharmacologic treatment underline the importance of screening for patients who are at risk for advanced fibrosis as they are most likely to benefit from new drug classes, such as the liver-directed thyroid receptor agonist resmiterom.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD), is a leading cause of chronic liver disease, affecting up to 30% of the global population. MASLD is strongly associated with metabolic risk factors such as obesity and type 2 diabetes, and can progress to advanced stages including cirrhosis and hepatocellular carcinoma. Early diagnosis and accurate staging of fibrosis are critical in managing the disease and preventing complications. While liver biopsy has long been considered the gold standard for assessing fibrosis, it is invasive and carries associated risks. In response, non-invasive tests (NITs) have emerged as essential alternatives for the diagnosis and monitoring of MASLD. Key methods include blood-based biomarkers such as the Fibrosis-4 (FIB-4) score, NAFLD Fibrosis Score (NFS), and Enhanced Liver Fibrosis (ELF) test, as well as imaging modalities like vibration-controlled transient elastography (VCTE) and magnetic resonance elastography (MRE). These tests provide safer, more accessible methods for identifying liver fibrosis and guiding clinical management. They are integral in assessing disease severity, guiding treatment decisions, and monitoring disease progression, particularly in light of emerging therapies. NITs have become increasingly recommended by clinical guidelines as they reduce the need for invasive procedures like liver biopsy, improving patient care and outcomes. In conclusion, non-invasive testing plays a crucial role in the effective management of MASLD, offering reliable alternatives for diagnosis and monitoring while minimizing risks associated with traditional invasive methods.

Background and Aims: Multiple non-invasive tests (NITs) for identifying advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) are available, but, due to the limitations of single NITs, the American Association for the Study of Liver Disease (AASLD) guidelines suggest a two-step strategy, combining the Fibrosis-4 Index (FIB-4) score with the Enhanced Liver Fibrosis (ELF) test to improve diagnostic accuracy and minimize unnecessary liver biopsies. However, few real-world studies have used such a sequential approach. We here evaluated the diagnostic accuracy of the ELF test in patients with recently established metabolic dysfunction-associated steatotic liver disease (MASLD) and assessed the clinical utility of applying a two-step strategy, including the ELF test following the FIB-4 score assessment, in patients with MASLD. Methods: We enrolled 153 patients diagnosed with MASLD who underwent liver biopsy at the Dong-A University Hospital between June 2018 and August 2023. The degree of fibrosis was determined based on liver biopsy results. Various NITs were used, including the Aminotransferase-to-Platelet Ratio Index (APRI), FIB-4 score, NAFLD Fibrosis score (NFS) and ELF test. The diagnostic efficacy of these NITs was evaluated based on the area under the receiver operating characteristic curve (AUROC). Additionally, the performance of each test was further examined both when applied individually and in a two-step approach, where FIB-4 was used followed by ELF testing. Key metrics such as sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were used for this analysis. Results: Overall, 153 patients with MASLD (mean age: 46.62 years; 52.3% men; 28.1% with type 2 diabetes) were included. The performance of the NITs in identifying advanced fibrosis was as follows: the AUROC of the APRI, FIB-4, NFS, and ELF tests were 0.803 (95% confidence interval (CI), 0.713-0.863), 0.769 (95% CI, 0.694-0.833), 0.699 (95% CI, 0.528-0.796), and 0.829 (95% CI, 0.760-0.885), respectively. The combination of the FIB-4 score ≥ 1.30 and the ELF score ≥ 9.8 showed 67.86% sensitivity, 90.40% specificity, a PPV of 75.18%, an NPV of 86.78%, an accuracy of 83.64%, and an AUROC of 0.791 for predicting the diagnosis of advanced fibrosis. This approach excluded 28 patients (71.8%) from unnecessary liver biopsies. Conclusions: Our study demonstrated that ELF testing maintained diagnostic accuracy in assessing liver fibrosis in patients with MASLD in real-world practice. This test was used as a second step in the evaluation, reducing clinically unnecessary invasive liver biopsies and referrals to tertiary institutions. This approach allows assessment of MASLD severity in primary care settings without requiring additional equipment.

Background: The Fibrosis-4 (FIB-4) index is widely recommended as a first-tier method for screening advanced hepatic fibrosis; however, its diagnostic performance is known to be suboptimal in patients with Type 2 diabetes mellitus (T2DM). We aim to propose a modified FIB-4, using the parameters of the existing FIB-4, tailored specifically for diabetic patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: A total of 1503 patients who underwent liver biopsy were divided into T2DM (n = 517) and non-T2DM (n = 986) groups. The model was developed using multiple regression analysis in the derivation cohort and validated in the validation cohort. Diagnostic accuracy was evaluated using the area under the receiver operating characteristic (AUC) curves. Results: Among the 1503 individuals, those with T2DM were older, more likely to be male, and had a higher prevalence of advanced hepatic fibrosis (≥F3) compared to non-T2DM individuals. Independent risk factors for advanced fibrosis in T2DM included age, AST, AST/ALT ratio, albumin, triglycerides, and platelet count. The optimized FIB-4 model for T2DM with MASLD (Diabetes Fibrosis Index) demonstrated superior diagnostic accuracy (AUC 0.771) compared to the FIB-4 (AUC 0.735, p = 0.012). The model showed a higher negative predictive value than the original FIB-4 across all age groups in the diabetic group. Conclusions: The newly optimized FIB-4 model for T2DM with MASLD (Diabetes Fibrosis Index), incorporating a non-linear predictive model, improves diagnostic performance (AUC) and the negative predictive value in MASLD with T2DM.

The global incidence of nonalcoholic fatty liver disease (NAFLD) is escalating considerably. NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis, which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix, leading to fibrosis. Hepatocyte ballooning is a key catalyst for fibrosis progression, potentially advancing to cirrhosis and its decompensated state. Fibrosis is a critical prognostic factor for outcomes in patients with NAFLD; therefore, those with substantial fibrosis require timely intervention. Although liver biopsy is the most reliable method for fibrosis detection, it is associated with certain risks and limitations, particularly in routine screening. Consequently, various noninvasive diagnostic techniques have been introduced. This review examines the increasing prevalence of NAFLD, evaluates the noninvasive diagnostic techniques for fibrosis, and assesses their efficacy in staging the disease. In addition, it critically appraises current and emerging antifibrotic therapies, focusing on their mechanisms, efficacy, and potential in reversing fibrosis. This review underscores the urgent need for effective therapeutic strategies, given the dire consequences of advanced fibrosis.

Steatotic liver disease is the overarching term for conditions characterised by abnormal lipid accumulation in the liver (liver or hepatic steatosis). Steatotic liver disease encompasses what was previously termed non-alcoholic fatty liver disease (NAFLD), which is now called metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, steatotic liver disease includes alcohol-related liver disease (ALD) and MetALD, the new classification for the overlap between MASLD and ALD, and rare causes of liver steatosis. Cirrhosis is globally the 11th leading cause of death, and steatotic liver disease has become the leading cause of cirrhosis in the EU and USA. Steatotic liver disease affects around 30% of the global population and is mainly driven by obesity, type 2 diabetes, and alcohol intake, but only a minor proportion with steatotic liver disease progress to cirrhosis. The presence and progression of liver fibrosis led by hepatic inflammation is the main predictor of liver-related death across the entire spectrum of steatotic liver diseases. A combination of recent advancements of widely available biomarkers for early detection of liver fibrosis together with considerable advancements in therapeutic interventions offer the possibility to reduce morbidity and mortality in patients with steatotic liver disease. This Seminar covers the recent reclassification of steatotic liver disease and how it reflects clinical practice and prognosis. For early detection of liver fibrosis, we propose a collaborative diagnostic framework between primary care and liver specialists. Lastly, we discuss current best practices for managing steatotic liver disease, we explore therapeutic targets across the spectrum of steatotic liver diseases, and we review the pipeline of drugs in development for MASLD.

Although metabolic dysfunction-associated steatohepatitis (MASH) is rapidly becoming a leading cause of cirrhosis worldwide, therapeutic options are limited and the number of clinical trials in MASH-related compensated cirrhosis is low as compared to those conducted in earlier disease stages. Moreover, designing clinical trials in MASH cirrhosis presents a series of challenges regarding the understanding and conceptualization of the natural history, regulatory considerations, inclusion criteria, recruitment, end points and trial duration, among others. The first international workshop on the state of the art and future direction of clinical trials in MASH-related compensated cirrhosis was held in April 2023 at Vall d'Hebron University Hospital in Barcelona (Spain) and was attended by a group of international experts on clinical trials from academia, regulatory agencies and industry, encompassing expertise in MASH, cirrhosis, portal hypertension, and regulatory affairs. The presented Roadmap summarizes important content of the workshop on current status, regulatory requirements and end points in MASH-related compensated cirrhosis clinical trials, exploring alternative study designs and highlighting the challenges that should be considered for upcoming studies on MASH cirrhosis.

Intravoxel incoherent motion (IVIM) diffusion weighted MRI (DWI) has potential for evaluating hepatic fibrosis but image acquisition technique influence on diffusion parameter estimation bears investigation.

To minimize variability and maximize repeatably in abdominal DWI in terms of IVIM parameter estimates.

Prospective test-retest and image quality comparison.

Healthy volunteers (3F/7M, 29.9 ± 12.9 years) and Family Study subjects (18F/12M, 51.7 ± 16.7 years), without and with liver steatosis.

Abdominal single-shot echo-planar imaging (EPI) and simultaneous multi-slice (SMS) DWI sequences with respiratory triggering (RT), breath-holding (BH), and navigator echo (NE) at 3 Tesla.

SMS-BH, EPI-NE, and SMS-RT data from twice-scanned healthy volunteers were analyzed using 6 × b-values (0-800 s⋅mm-2) and lower (LO) and higher (HI) b-value ranges. Family Study subjects were scanned using SMS and standard EPI sequences. The biexponential IVIM model was used to estimate fast-diffusion coefficient (Df), fraction of fast diffusion (f), and slow-diffusion coefficient (Ds). Scan time, estimated signal-to-noise ratio (eSNR), eSNR per acquisition, and distortion ratio were compared.

Coefficients of variation (CoV) and Bland Altman analyses were performed for test-retest repeatability. Interclass correlation coefficient (ICC) assessed interobserver agreement with P < 0.05 deemed significant.

Within-subject CoVs among volunteers (N = 10) for f and Ds were lowest in EPI-NE-LO (11.6%) and SMS-RT-HI (11.1%). Inter-observer ICCs for f and Ds were highest for EPI-NE-LO (0.63) and SMS-RT-LO (0.76). Df could not be estimated for most subjects. Estimated eSNR (EPI = 21.9, SMS = 4.7) and eSNR time (EPI = 6.7, SMS = 16.6) were greater for SMS, with less distortion in the liver region (DR-PE: EPI = 23.6, SMS = 13.1).

Simultaneous multislice acquisitions had significantly less variability and higher ICCs of Ds, higher eSNR, less distortion, and reduced scan time compared to EPI.

2 TECHNICAL EFFICACY: Stage 1.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease in the world and was recently renamed to emphasize its metabolic component.

This article seeks to fill the gap in specific guidelines for patients with obesity and MASLD who will undergo bariatric surgery.

A systematic search for guidelines was carried out on PubMed and Embase platforms.

A total of 544 articles were found, of which 11 were selected according to inclusion and exclusion criteria. All 11 guidelines are from clinical societies; therefore, they do not include some necessary interpretations for bariatric patients.

We recommend that every patient undergoing bariatric and metabolic surgery be screened initially with the Fibrosis-4 (FIB-4) score, followed by transient hepatic elastography (vibration-controlled transient elastography, VCTE), especially for those with FIB-4>1.3. However, interpreting VCTE results in obese patients requires further studies to define the actual cutoff values. Enhanced Liver Fibrosis® shows promise but its availability is limited. The indication for liver biopsy during surgery needs to be individualized but it is recommended for those with changes in FIB-4 and/or VCTE. Family screening is recommended for relatives of young patients with already advanced fibrosis. Liver transplantation is an option for patients with advanced MASLD but the optimal timing for bariatric surgery with transplantation is still unclear. Regular follow-up and VCTE examination are recommended to monitor disease progression after surgery.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide, making it the leading cause of liver related morbidity and mortality. Currently, liver biopsy is the gold standard for assessing individuals with steatohepatitis and fibrosis. However, its invasiveness, sampling variability, and impracticality for large-scale screening has driven the search for non-invasive methods for early diagnosis and staging. In this review, we comprehensively summarise the evidence on the diagnostic performance and limitations of existing non-invasive serum biomarkers and scores in the diagnosis and evaluation of steatosis, steatohepatitis, and fibrosis.

Several non-invasive serum biomarkers and scores have been developed over the last decade, although none has successfully been able to replace liver biopsy. The introduction of new NAFLD terminology, namely metabolic dysfunction-associated fatty liver disease (MAFLD) and more recently metabolic dysfunction-associated steatotic liver disease (MASLD), has initiated a debate on the interchangeability of these terminologies. Indeed, there is a need for more research on the variability of the performance of non-invasive serum biomarkers and scores across the diagnostic entities of NAFLD, MAFLD and MASLD. There remains a significant need for finding valid and reliable non-invasive methods for early diagnosis and assessment of steatohepatitis and fibrosis to facilitate prompt risk stratification and management to prevent disease progression and complications. Further exploration of the landscape of MASLD under the newly defined disease subtypes is warranted, with the need for more robust evidence to support the use of commonly used serum scores against the new MASLD criteria and validation of previously developed scores.

In response to the growing health crisis of liver-related morbidity and mortality, screening for liver cirrhosis has emerged as a promising strategy for early detection and timely intervention. By identifying individuals with severe fibrosis or compensated cirrhosis, screening holds the promise of enhancing treatment outcomes, delaying disease progression, and ultimately improving the quality of life of affected individuals. Clinical practice guidelines from international scientific societies currently recommend targeted screening strategies, investigating high-risk populations with known risk factors of liver disease. While there is good evidence that screening increases case finding in the population, and a growing number of studies indicate that screening may motivate beneficial lifestyle changes in patients with steatotic liver disease, there are major gaps in knowledge in need of clarification before screening programs of cirrhosis are implemented. Foremost, randomized trials are needed to ensure that screening leads to improved liver-related morbidity and mortality. If not, screening for cirrhosis could be unethical due to overdiagnosis, overtreatment, increased health care costs, negative psychological consequences of screening, and futile invasive investigations. Moreover, the tests used for screening need to be optimized toward lower false positive rates than the currently used FIB-4 while retaining few false negatives. Finally, barriers to adherence to screening and implementation of screening programs need to be elucidated. This review provides a comprehensive overview of the current landscape of screening strategies for liver cirrhosis and the promises and pitfalls of current methods for early cirrhosis detection.

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 new nomenclature of metabolic dysfunction-associated steatotic liver disease (MASLD) emphasizes a positive diagnosis based on cardiometabolic risk factors. This definition is not only less stigmatizing but also allows for subclassification and stratification, thereby addressing the heterogeneity of what was historically referred to as nonalcoholic fatty liver disease. The heterogeneity within this spectrum is influenced by several factors which include but are not limited to demographic/dietary factors, the amount of alcohol use and drinking patterns, metabolic status, gut microbiome, genetic predisposition together with epigenetic factors. The net effect of this dynamic and intricate system-level interaction is reflected in the phenotypic presentation of MASLD. Therefore, the application of precision medicine in this scenario aims at complex phenotyping with consequent individual risk prediction, development of individualized preventive strategies, and improvements in the clinical trial designs. In this review, we aim to highlight the importance of precision medicine approaches in MASLD, including the use of novel biomarkers of disease, and its subsequent utilization in future study designs.

Previous studies, including our own, have demonstrated that arsenic exposure can induce liver fibrosis, while the underlying mechanism remains unclear and there is currently no effective pharmacological intervention available. Recent research has demonstrated that vitamin D supplementation can ameliorate liver fibrosis caused by various etiologies, potentially through modulation of the Nrf2 signaling pathways. However, it remains unclear whether vitamin D intervention can mitigate arsenic-caused liver fibrosis. As is known hepatic stellate cells (HSCs) activation and extracellular matrix (ECM) deposition are pivotal in the pathogenesis of liver fibrosis. In this study, we investigated the intervention effect of calcitriol (a form of active vitamin D) on arsenite-triggered Lx-2 cells (a human hepatic stellate cell line) activation and ECM oversecretion. Additionally, we also elucidated the role and mechanism of Nrf2 antioxidant signaling pathway. Our results demonstrated that calcitriol intervention significantly inhibits Lx-2 cell activation and ECM oversecretion induced by arsenite exposure. Additionally, calcitriol activates Nrf2 and its downstream antioxidant enzyme expression in Lx-2 cells, thereby reducing ROS overproduction caused by arsenite exposure. Further investigation reveals that calcitriol activates the Nrf2 signaling pathway and inhibits arsenite-triggered Lx-2 cell activation and ECM oversecretion by targeting vitamin D receptor (VDR). In conclusion, this study has demonstrated that vitamin D intervention can effectively inhibit HSC activation and ECM oversecretion triggered by arsenite exposure through its antioxidant activity. This provides a novel strategy for targeted nutritional intervention in the treatment of arsenic-induced liver fibrosis.

Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions of 22.8% and 24.2% with retatrutide 8 and 12 mg, respectively. The primary objective of this substudy was to assess mean relative change from baseline in liver fat (LF) at 24 weeks in participants from that study with metabolic dysfunction-associated steatotic liver disease and ≥10% of LF. Here, in this randomized, double-blind, placebo-controlled trial, participants (n = 98) were randomly assigned to 48 weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg dose) or placebo. The mean relative change from baseline in LF at 24 weeks was -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg), -82.4% (12 mg) and +0.3% (placebo) (all P < 0.001 versus placebo). At 24 weeks, normal LF (<5%) was achieved by 27% (1 mg), 52% (4 mg), 79% (8 mg), 86% (12 mg) and 0% (placebo) of participants. LF reductions were significantly related to changes in body weight, abdominal fat and metabolic measures associated with improved insulin sensitivity and lipid metabolism. The ClinicalTrials.gov registration is NCT04881760 .