Little is known about the associations between changes in hepatic steatosis and changes in abdominal adiposity after metabolic bariatric surgery.

To evaluate the serial changes in hepatic steatosis and abdominal adiposity following sleeve gastrectomy (SG).

University hospital, Taiwan.

In this prospective study, patients who underwent SG and intraoperative liver biopsy were enrolled. Magnetic resonance imaging (MRI) was performed to assess the liver fat fraction (LFF), visceral adipose tissue (VAT) area, and subcutaneous adipose tissue (SAT) area. Liver fibrosis was assessed preoperatively via biopsy and the fibrosis-4 index (FIB-4) and postoperatively with the FIB-4.

Seventy-six metabolic dysfunction-associated steatotic liver disease (MASLD) patients, including 67 pure MASLD patients and 9 MASLD patients with combined etiologies, were enrolled. LFF and visceral-to-subcutaneous fat ratio were associated with metabolic dysfunction-associated steatohepatitis, and VAT area was associated with significant fibrosis (≥F2). Twelve months after SG, all MRI measurements significantly improved. The median LFF of pure MASLD patients decreased from 17.4% at baseline to 4.2% and 3.7% at the 6th and 12th postoperative months, respectively. Complete resolution of steatosis was achieved in 97.5% of patients at the 12th postoperative months. Using %VAT and %SAT reductions at the sixth postoperative month as references, LFF decreased more rapidly, with fold ratios of 1.3 and 1.8, respectively.

SG resulted in a significant decrease in hepatic steatosis and abdominal adiposity in patients with severe obesity, but hepatic steatosis improved faster than abdominal adiposity. Hepatic steatosis resolved in almost all patients 12 months after SG.

Metabolic dysfunction-associated steatohepatitis (MASH) is associated with a >10-fold increase in liver-related mortality. However, biomarkers predicting both MASH and mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are missing. We developed a metabolome-derived prediction score for MASH and examined whether it predicts mortality in Chinese and European cohorts.

The MASH prediction score was developed using a multi-step machine learning strategy, based on 44 clinical parameters and 250 serum metabolites measured by proton nuclear magnetic resonance in 311 Chinese adults undergoing a liver biopsy. External validation was conducted in a Finnish liver biopsy cohort (n = 305). We investigated associations of the score with all-cause and cause-specific mortality in the population-based Shanghai Changfeng study (n = 5,893) and the UK biobank (n = 111,673).

A total of 24 clinical parameters and 194 serum metabolites were significantly associated with MASH in the Chinese liver biopsy cohort. The final MASH score included BMI, aspartate aminotransferase, tyrosine, and the phospholipid-to-total lipid ratio in VLDL. The score identified patients with MASH with AUROCs of 0.87 (95% CI 0.83-0.91) and 0.81 (95% CI 0.75-0.88) in the Chinese and Finnish cohorts, with high negative predictive values. Participants with a high or intermediate risk of MASH based on the score had a markedly higher risk of MASLD-related mortality than those with a low risk in Chinese (hazard ratio 23.19; 95% CI 4.80-111.97) and European (hazard ratio 20.15; 95% CI 10.95-37.11) individuals after 7.2 and 12.6 years of follow-up, respectively. The MASH prediction score was superior to the Fibrosis-4 index and the NAFLD fibrosis score in predicting MASLD-related mortality.

The metabolome-derived MASH prediction score accurately predicts risk of MASH and MASLD-related mortality in both Chinese and European individuals.

Metabolic dysfunction-associated steatohepatitis (MASH) is associated with more than a 10-fold increase in liver-related death. However, biomarkers predicting not only MASH, but also death due to liver disease, are missing. We established a MASH prediction score based on 44 clinical parameters and 250 serum metabolites using a machine learning strategy. This metabolome-derived MASH prediction score could accurately identify patients with MASH among both Chinese and Finnish individuals, and it was superior to the Fibrosis-4 index and the NAFLD fibrosis score in predicting MASLD-related death in the general population. Thus, the new MASH prediction score is a useful tool for identifying individuals with a markedly increased risk of serious liver-related outcomes among at-risk and general populations.

We present an isotope-based metabolic flux analysis (MFA) approach to simultaneously quantify metabolic fluxes in the liver, heart, and skeletal muscle of individual mice. The platform was scaled to examine metabolic flux adaptations in age-matched cohorts of mice exhibiting varying levels of chronic obesity. We found that severe obesity increases hepatic gluconeogenesis and citric acid cycle flux, accompanied by elevated glucose oxidation in the heart that compensates for impaired fatty acid oxidation. In contrast, skeletal muscle fluxes exhibit an overall reduction in substrate oxidation. These findings demonstrate the dichotomy in fuel utilization between cardiac and skeletal muscle during worsening metabolic disease and demonstrate the divergent effects of obesity on metabolic fluxes in different organs. This multi-tissue MFA technology can be extended to address important questions about in vivo regulation of metabolism and its dysregulation in disease, which cannot be fully answered through studies of single organs or isolated cells/tissues.

Improved image quality, better scanners, innovative software technologies, enhanced computational power, superior network connectivity, and the ease of virtual image reproduction and distribution are driving the potential use of digital pathology for diagnosis and education. Although relatively common in clinical oncology, its application in liver pathology is under development. Digital pathology and improving subjective histologic scoring systems could be essential in managing obesity-associated steatotic liver disease. The increasing use of digital pathology in analyzing liver specimens is particularly intriguing as it may offer a more detailed view of liver biology and eliminate the incomplete measurement of treatment responses in clinical trials. The objective and automated quantification of histological results may help establish standardized diagnosis, treatment, and assessment protocols, providing a foundation for personalized patient care. Our experience with artificial intelligence (AI)-based software enhances reproducibility and accuracy, enabling continuous scoring and detecting subtle changes that indicate disease progression or regression. Ongoing validation highlights the need for collaboration between pathologists and AI developers. Concurrently, automated image analysis can address issues related to the historical failure of clinical trials stemming from challenges in histologic assessment. We discuss how these novel tools can be incorporated into liver research and complement post-diagnosis scenarios where quantification is necessary, thus clarifying the evolving role of digital pathology in the field.

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.

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.

This study aims to identify the most accurate and useful non-invasive method to replace liver biopsy for the diagnosis of non-alcoholic fatty liver disease (NAFLD) before bariatric surgery and postoperative follow-up in morbidly obese patients.

This single-center study is a retrospective analysis of prospectively collected data from 68 morbidly obese patients who underwent laparoscopic sleeve gastrectomy with intraoperative liver biopsy. Preoperative non-invasive diagnostic methods, including fatty liver index, NAFLD fibrosis score, enhanced liver fibrosis score, FibroScan, magnetic resonance imaging-proton density fat fraction (MRI-PDFF), magnetic resonance spectroscopy (MRS)-PDFF, and magnetic resonance elastography (MRE) were compared against liver biopsy results. Diagnostic performance was assessed using Spearman's correlation and receiver operating characteristic (ROC) curve analysis.

Liver biopsy confirmed the presence of steatosis in 92.7% of patients, Nonalcoholic Steatohepatitis (NASH) in 64.7%, and liver fibrosis (≥F1) in 72.0%. MRI-PDFF and MRS-PDFF demonstrated the highest diagnostic accuracy for NASH, with the strongest correlation with histological findings. For liver fibrosis, MRE showed the strongest correlation with histological fibrosis stage, while FibroScan-Liver Stiffness Measurement (LSM) demonstrated better diagnostic performance in ROC analysis. However, the overall diagnostic quality of non-invasive methods for fibrosis assessment remained modest, with no method achieving a quality value above 0.6.

MRI-PDFF and MRS-PDFF were the most accurate noninvasive methods for diagnosing NASH in morbidly obese patients. For liver fibrosis, FibroScan-LSM may be more suitable for detection, while MRE may better reflect fibrosis severity. Further studies are needed to assess the cost-effectiveness and clinical applicability of these methods.

Hepatic steatosis, characterized by fat accumulation in hepatocytes, can result from metabolic dysfunction-associated steatotic liver disease (MASLD), infections, alcoholism, chemotherapy, and toxins. MASLD is diagnosed via imaging or biopsy with metabolic criteria and may progress to metabolic dysfunction-associated steatohepatitis, potentially leading to fibrosis, cirrhosis, or cancer. The coexistence of hepatic steatosis with chronic hepatitis B (CHB) is mainly related to metabolic factors and increases mortality and cancer risks. As a noninvasive method, attenuation imaging (ATI) shows promise in quantifying liver fat, demonstrating strong correlation with liver biopsy.

To investigate the disparity of ATI for assessing biopsy-based hepatic steatosis in CHB patients and MASLD patients.

The study enrolled 249 patients who underwent both ATI and liver biopsy, including 78 with CHB and 171 with MASLD. Hepatic steatosis was classified into grades S0 to S3 according to the proportion of fat cells present. Liver fibrosis was staged from 0 to 4 according to the meta-analysis of histological data in viral hepatitis scoring system. The diagnostic performance of attenuation coefficient (AC) values across different groups was compared for each grade of steatosis. Factors associated with the AC values were determined through linear regression analysis. A multivariate logistic regression model was established to predict ≥ S2 within the MASLD group.

In both the CHB and the MASLD groups, AC values increased significantly with higher steatosis grade (P < 0.001). In the CHB group, the areas under the curve (AUCs) of AC for predicting steatosis grades ≥ S1, ≥ S2 and S3 were 0.918, 0.960 and 0.987, respectively. In contrast, the MASLD group showed AUCs of 0.836, 0.774, and 0.688 for the same steatosis grades. The diagnostic performance of AC for detecting ≥ S2 and S3 indicated significant differences between the two groups (both P < 0.001). Multivariate linear regression analysis identified body mass index, triglycerides, and steatosis grade as significant factors for AC. When the steatosis grade is ≥ S2, it can progress to more serious liver conditions. A clinical model integrating blood biochemical parameters and AC was developed in the MASLD group to enhance the prediction of ≥ S2, achieving an AUC of 0.848.

The AC could effectively discriminate the degree of steatosis in both the CHB and MASLD groups. In the MASLD group, when combined with blood biochemical parameters, AC exhibited better predictive ability for moderate to severe steatosis.

Lanifibranor, a pan-peroxisome proliferator-activated receptor agonist, has demonstrated therapeutic efficacy on metabolic dysfunction-associated steatohepatitis (MASH) resolution and fibrosis improvement in the Phase IIb NATIVE study. The histologic endpoints of MASH resolution and fibrosis improvement (E1), MASH resolution without worsening of fibrosis (E2), and fibrosis improvement without worsening of MASH (E3) were investigated with the aim of identifying biological signatures of E1, E2, and E3 responders based on serum biomarkers in patients treated with lanifibranor.

NATIVE evaluated lanifibranor 800 and 1200 mg daily vs placebo in patients with non-cirrhotic MASH treated over 24 weeks. Liver biopsy was obtained at baseline and the end of treatment. Patients receiving lanifibranor were pooled, and those with liver biopsies were selected (n = 142). A panel of 65 biomarkers were evaluated by assessing baseline and absolute as well as relative changes at the end of treatment.

The biomarkers included in E1 score (baseline adiponectin and ferritin; delta of matrix metalloproteinase 9 and transferrin), E2 score (baseline cytokeratin 18 Fragment M65; delta of hyaluronic acid, fructosamine, and alanine aminotransferase), and E3 score (baseline cytokeratin 18 Fragment M65 and gamma-glutamyl transferase; delta of aspartate aminotransferase, insulin, and urea) represented metabolic, apoptotic, and fibrosis aspects of the disease. These signatures provided good accuracy for the noninvasive identification of histologic response under lanifibranor with area under the receiver operating characteristic curve at 0.81 ± 0.08 for E1 score, 0.80 ± 0.08 for E2 score, and 0.81 ± 0.08 for E3 score.

Results from this analysis show evidence that baseline values and changes in selected serum biomarkers can aid in predicting histologic response in MASH under lanifibranor treatment. These findings support utilizing a similar approach in a larger sample size (NATiV3, NCT03008070).

During the coronavirus disease 2019 (COVID-19) pandemic, there was a marked increase in alcohol consumption. COVID-19 superimposed on underlying liver disease notably worsens the outcome of many forms of liver injury. The goal of a current pilot study was to test the dual exposure of alcohol and COVID-19 infection in an experimental animal model of alcohol-associated liver disease (ALD).

After 4 weeks of ethanol (EtOH) feeding, C57BL/6 male mice received SARS-CoV-2 (SARS2-N501YMA30) intranasally at 3 × 102, 1 × 103, 3 × 103, and 1 × 104 plaque-forming units (PFU). Mice were then weighed/monitored daily for morbidity/mortality for 10 days while continuing EtOH consumption. Markers of liver inflammation, injury, and intestinal barrier integrity were evaluated.

A similar gradual weight loss was observed in all inoculated mice (slightly less in the 3 × 102 group) up to post-infection day 4. Greater mortality was observed in mice receiving the highest viral dose at days 3 and 4 post-infection. The majority of the surviving mice subjected to EtOH and inoculated with 3 × 103 or 1 × 104 PFU rapidly lost 25% of their body weight and were euthanized on post-infection day 4. Analysis of liver health in animals that survived to the end of the experiment exhibited no significant changes in hepatic steatosis but had a limited increase in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at all viral doses versus EtOH alone. However, the 1 × 104 PFU viral dose exacerbated EtOH-induced hepatic inflammation characterized by elevated levels of several pro-inflammatory cytokines, including Il-6 and Tnf-α. There was limited effect of viral infection on the intestine.

SARS-CoV-2 infection caused a dose-dependent negative impact on body weight and survival in mice fed EtOH. This pilot study suggests that early mortality observed after high-dose SARS-CoV-2 challenge could be due, in part, to hepatic dysfunction following chronic EtOH feeding.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of adults globally. Despite efforts to develop non-invasive diagnostic tools, liver biopsy remains the gold standard for diagnosing metabolic dysfunction-associated steatohepatitis (MASH) and assessing fibrosis. This study investigated RNA aptamer panels, selected using APTASHAPE technology, for non-invasive MASLD diagnosis and fibrosis stratification. Aptamer panels were selected in a cohort of individuals with MASLD (development cohort, n = 77) and tested in separate cohorts: one with MASLD (test cohort, n = 57) and one assessed for bariatric surgery (bariatric cohort, n = 62). A panel distinguishing MASLD without steatohepatitis from MASH accurately stratified individuals in the developmentcohort (AUC = 0.83) but failed in the test and bariatric cohorts. It did, however, distinguish healthy controls from individuals with MASLD, achieving an AUC of 0.72 in the test cohort. A panel for fibrosis stratification differentiated F0 from F3-4 fibrosis in the development cohort (AUC = 0.68) but not in other cohorts. Mass spectrometry identified five plasma proteins as potential targets of the discriminative aptamers, with complement factor H suggested as a novel MASLD biomarker. In conclusion, APTASHAPE shows promise as a non-invasive tool for diagnosing and staging MASLD and identifying associated plasma biomarkers.

We aimed to elucidate the value of ultrasound-based biomarkers for predicting the major life-threatening events in metabolic dysfunction-associated steatotic liver disease (MASLD). We established a prospective cohort of 279 patients who underwent two-dimensional shear wave elastography (2D-SWE), ultrasound-guided attenuation parameter (UGAP). An area under the curve analysis was performed to determine the cutoff values of liver stiffness measurements (LSM) by 2D-SWE and attenuation coefficient (AC) by UGAP for a moderate fibrosis and a moderate steatosis. We then classified the cohort into Groups A (low LSM and low AC), B (low LSM and high AC), C (high LSM and high AC), and D (high LSM and low AC). We compared the incidence of events between the groups, and estimated the hazard ratios (HRs) with 95% confidence intervals (CIs). The LSM and AC cut off values were 8.37 kPa and 0.62 dB/cm/MHz, respectively. The cumulative incidence rate in Groups A, B, C, and D were 11.2%, 12.2%, 29.5%, and 31.0%/5years, respectively (p < 0.05). LSM (HRs = 1.20, 95%CIs: 1.09-1.32, p < 0.01), and AC (HRs = 1.62, 95%CIs: 1.04-2.51, p = 0.03) were associated with life-threatening events. A combination of 2D-SWE and UGAP may help identify patients with MASLD at high risk for subsequent life-threatening events.

Multinodular steatosis represents a relatively uncommon manifestation of fatty liver disease (FLD). Co-morbidities such as metabolic syndrome or cirrhosis are often associated. Despite typical features of imaging (ultrasound, CT, and MRI), core biopsy sometimes remains the gold standard for diagnosis. We describe the case of a 57-year-old male patient with a long history of hepatic cirrhosis and a recent diagnosis of carcinoma of the tongue, successfully treated. Due to the occurrence of nausea, diarrhea and jaundice the patient is admitted to Our Hospital where ultrasound examination and contrast-enhanced CT are performed, showing global hypoechogenicity of the liver parenchyma with multiple hypo-attenuating lesions. To rule out metastatic lesions, contrast-enhanced CT of the thorax and cranium and gastroscopy and colonoscopy are performed, with no evidence of primary malignancy. Core biopsy reveals macro-vacuolar steatosis within a cirrhotic liver with regenerative aspects.

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.

As an opportunistic bacterial pathogen, Klebsiella pneumoniae (KP) is prone to causing a spectrum of diseases in rabbits when their immune system is compromised, which poses a threat to rabbit breeding industry. Bacillus coagulans (BC), recognized as an effective probiotic, confers a variety of benefits including anti-inflammatory and antioxidant properties.

The purpose of this study was to investigate whether dietary BC can effectively alleviate hepatic injury caused by KP.

In this study, the rabbits were initially pretreated with varying doses of BC (1×106, 5×106, and 1×107 CFU/g), followed by a challenge with KP at a concentration of 1011 CFU/mL. Liver tissues were harvested and processed for histological assessment using H&E and VG stains to assess structural alterations. Biochemical assays were employed to quantify the enzymatic activities of T-SOD and GSH-Px, as well as the MDA content. Furthermore, ELISA was utilized to detect the levels of inflammatory cytokine (IL-10, IL-6, IL-1β and TNF-α) and apoptotic-related gene (Bcl-2, Bax).

Morphological observation indicated that BC can effectively mitigate KP-induced hepatic sinusoidal dilatation and congestion, as well as ameliorate the degree of hepatic fibrosis. Further analysis showed that BC significantly lowered MDA level in KP-treated rabbits, while enhanced the activities of T-SOD and GSH-Px. Additionally, ELISA result showed that BC pretreatment significantly reduced the levels of pro-inflammatory cytokines TNF-a, IL-6, IL-1β and pro-apoptotic gene Bax, while increasing the levels of anti-inflammatory cytokine IL-10 and anti-apoptotic gene Bcl-2 in KP-treated rabbits.

Above data indicate that BC supplementation effectively attenuated oxidative stress and inflammatory response induced by KP through augmenting the activities of antioxidant enzymes and diminishing the levels of pro-inflammatory factors. Furthermore, it reduced the Bax/Bcl-2 ratio in the liver, thereby inhibiting KP-induced apoptosis. The treatment group receiving 5x106 CFU/g BC benefitted most from the protective effect.

Obesity and prediabetes affect a substantial part of the general population, but are largely underdiagnosed, underestimated, and undertreated. Prediabetes differs from diabetes only in the degree of hyperglycaemia consequent to the progressive decline in residual beta-cell function. Both prediabetes and diabetes occur as a consequence of insulin resistance that starts several years before the clinical onset of overt diabetes. Macrovascular complications in patients with diabetes are mainly caused by insulin resistance. This is why in prediabetes, the overall cardiovascular risk is, by all means, similar to that in patients with diabetes. It is important, therefore, to identify prediabetes and treat patients not only to prevent or delay the onset of diabetes, but to reduce the cardiovascular risk associated with prediabetes. This review provides an overview of the pathophysiology of prediabetes in patients with obesity and the progression toward overt diabetes. We have reviewed nutritional and pharmacological approaches to the management of obesity and reduced glucose tolerance, and the treatment of the major comorbidities in these patients, including hypertension, dyslipidaemia, and Metabolic dysfunction-associated Steatotic Liver Disease (MASLD), has also been reviewed. In patients with obesity and prediabetes, the nutritional approach is similar to that adopted for patients with obesity and diabetes; treatments of dyslipidaemia and hypertension also have the same targets compared to patients with diabetes. MASLD is a critical issue in these patients; in the prediabetic state, MASLD rarely progresses into fibrosis. This highlights the importance of the early recognition of this pathological condition before patients become diabetic when the risk of fibrosis is much higher. It is necessary to raise awareness of the clinical relevance of this pathological condition in order to prompt early intervention before complications occur. The single most important therapeutic goal is weight loss, which must be early and persistent.

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).

Metabolic dysfunction-associated steatohepatitis (MASH) with bridging fibrosis is a critical stage in the evolution of fatty liver disease. Second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence (AI) provides sensitive and reproducible quantitation of liver fibrosis. This methodology was applied to gain an in-depth understanding of intra-stage fibrosis changes and septa analyses in a homogenous, well-characterised group with MASH F3 fibrosis.

Paired liver biopsies (baseline [BL] and end of treatment [EOT]) of 57 patients (placebo, n = 17 and tropifexor n = 40), with F3 fibrosis stage at BL according to the clinical research network (CRN) scoring, were included. Unstained sections were examined using SHG/TPEF microscopy with AI. Changes in liver fibrosis overall and in five areas of liver lobules were quantitatively assessed by qFibrosis. Progressive, regressive septa, and 12 septa parameters were quantitatively analysed.

qFibrosis demonstrated fibrosis progression or regression in 14/17 (82%) patients receiving placebo, while the CRN scoring categorised 11/17 (65%) as 'no change'. Radar maps with qFibrosis readouts visualised quantitative fibrosis dynamics in different areas of liver lobules even in cases categorised as 'No Change'. Measurement of septa parameters objectively differentiated regressive and progressive septa (p < .001). Quantitative changes in individual septa parameters (BL to EOT) were observed both in the 'no change' and the 'regression' subgroups, as defined by the CRN scoring.

SHG/TPEF microscopy with AI provides greater granularity and precision in assessing fibrosis dynamics in patients with bridging fibrosis, thus advancing knowledge development of fibrosis evolution in natural history and in clinical trials.

Metabolic disturbances are major contributors to the onset and progression of non-alcoholic fatty liver disease (NAFLD), which includes a histological spectrum ranging from single steatosis (SS) to non-alcoholic steatohepatitis (NASH). This study aimed to identify serum metabolites and lipids enriched in different histological stages of NAFLD and to explore metabolites/lipids as non-invasive biomarkers in risk prediction of NAFLD and NASH in obese Chinese.

Serum samples and liver biopsies were obtained from 250 NAFLD subjects. Untargeted metabolomic and lipidomic profiling were performed using Liquid Chromatography-Mass Spectrometry. Significantly altered metabolites and lipids were identified by MaAsLin2. Pathway enrichment was conducted with MetaboAnalyst and LIPEA. WGCNA was implemented to construct the co-expression network. Logistic regression models were developed to classify different histological stages of NAFLD.

A total of 263 metabolites and 550 lipid species were detected in serum samples. Differential analysis and pathway enrichment analysis revealed the progressive patterns in metabolic mechanisms during the transition from normal liver to SS and to NASH, including N-palmitoyltaurine, tridecylic acid, and branched-chain amino acid signaling pathways. The co-expression network showed a distinct correlation between different triglyceride and phosphatidylcholine species with disease severity. Multiple models classifying NAFLD versus normal liver and NASH versus SS identified important metabolic features associated with significant improvement in disease prediction compared to conventional clinical parameters.

Different histological stages of NAFLD are enriched with distinct sets of metabolites, lipids, and metabolic pathways. Integrated algorithms highlight the important metabolic and lipidomic features for diagnosis and staging of NAFLD in obese individuals.

This study aimed to identify the genetic risk factors from donors or recipients that contribute to postliver transplantation (LT) steatotic liver disease (SLD), focusing on the genetic risk score (GRS) based on single nucleotide polymorphisms (SNPs) in SLD patients.

This retrospective study included 55 Japanese SLD recipients and their respective donors. Genotyping of PNPLA3, TM6SF2, and HSD17B13 was undertaken, and the combined GRS was calculated. The relationship between the GRS and the incidence of posttransplant SLD was also evaluated.

The SLD recipients had a high prevalence of post-LT graft steatosis/steatohepatitis (76.4% and 58.2%, respectively). Although the recipients had a high frequency of risk alleles, there was no relationship between the number of risk alleles for each SNP and the incidence of posttransplant SLD. In contrast, an increased number of risk alleles for any SNP in the donor was correlated with high incidence rates of both post-LT steatosis and steatohepatitis. A multivariable analysis showed that a high donor GRS was an independent risk factor for graft steatosis (odds ratio 8.77; 95% CI, 1.94-52.94; p = 0.009). Similarly, a high donor GRS was an independent risk factor (odds ratio 6.76; 95% CI, 1.84-30.78; p = 0.007) for post-LT graft steatohepatitis.

Donor risk alleles of PNPLA3, TM6SF2, and HSD17B13, rather than recipient risk alleles, have been implicated in the development of posttransplant SLD. The combination of these donor risk alleles into a GRS could predict the development of posttransplant SLD.

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of liver-related morbidity and mortality. The diagnosis of non-alcoholic steatohepatitis (NASH) plays a crucial role in the management of NAFLD patients.

The aim of our observational study was to build a machine learning model to identify NASH in NAFLD patients.

The clinical characteristics of 259 NAFLD patients and their initial laboratory data (Cohort 1) were collected to train the model and carry out internal validation. We compared the models built by five machine learning algorithms and screened out the best models. Receiver operating characteristic (ROC) curves, sensitivity, specificity, and accuracy were used to evaluate the performance of the model. In addition, the NAFLD patients in Cohort 2 (n = 181) were externally verified.

We finally identified six independent risk factors for predicting NASH, including neutrophil percentage (NEU%), aspartate aminotransferase/alanine aminotransferase (AST/ALT), hematocrit (HCT), creatinine (CREA), uric acid (UA), and prealbumin (PA). The NASH-XGB6 model built using the XGBoost algorithm showed sufficient prediction accuracy, with ROC values of 0.95 (95 % CI, 0.91-0.98) and 0.90 (95 % CI, 0.88-0.93) in Cohort 1 and Cohort 2, respectively.

NASH-XGB6 can serve as an effective tool for distinguishing NASH patients from NAFLD patients.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health concern worldwide. Liver biopsy is the gold standard for diagnosing and staging MASLD, but it is invasive and carries associated risks. In recent years, there has been significant progress in developing noninvasive techniques for evaluation. This review article discusses briefly current available noninvasive assessments and the various liver biopsy techniques available for MASLD, including invasive techniques such as transjugular and transcutaneous needle biopsy, intraoperative/laparoscopic biopsy, and the evolving role of endoscopic ultrasound-guided biopsy. In addition to discussing the various biopsy techniques, we review the current state of knowledge on the histopathologic evaluation of MASLD, including the various scoring systems used to grade and stage the disease. We also explore current and alternative modalities for histopathologic evaluation, such as whole slide imaging and the utility of immunohistochemistry. Overall, this review article provides a comprehensive overview of the progress in liver biopsy techniques for MASLD and compares invasive and noninvasive modalities. However, beyond clinical trials, the practical application of liver biopsy may be limited, as ongoing advancements in noninvasive fibrosis assessments are expected to more effectively identify candidates for MASLD treatment in real-world settings.

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) is often asymptomatic and underdiagnosed; consequently, there is a demand for simple, non-invasive diagnostic tools. In this study, we developed a method to quantify liver steatosis based on miRNAs, present in liver and serum, that correlate with liver fat. The miRNAs were analyzed by miRNAseq in liver samples from two cohorts of patients with a precise quantification of liver steatosis. Common miRNAs showing correlation with liver steatosis were validated by RT-qPCR in paired liver and serum samples. Multivariate models were built using partial least squares (PLS) regression to predict the percentage of liver steatosis from serum miRNA levels. Leave-one-out cross validation and external validation were used for model selection and to estimate predictive performance. The miRNAseq results disclosed (a) 144 miRNAs correlating with triglycerides in a set of liver biobank samples (n = 20); and (b) 124 and 102 miRNAs correlating with steatosis by biopsy digital image and MRI analyses, respectively, in liver samples from morbidly obese patients (n = 24). However, only 35 miRNAs were common in both sets of samples. RT-qPCR allowed to validate the correlation of 10 miRNAs in paired liver and serum samples. The development of PLS models to quantitatively predict steatosis demonstrated that the combination of serum miR-145-3p, 122-5p, 143-3p, 500a-5p, and 182-5p provided the lowest root mean square error of cross validation (RMSECV = 1.1, p-value = 0.005). External validation of this model with a cohort of mixed MASLD patients (n = 25) showed a root mean squared error of prediction (RMSEP) of 5.3. In conclusion, it is possible to predict the percentage of hepatic steatosis with a low error rate by quantifying the serum level of five miRNAs using a cost-effective and easy-to-implement RT-qPCR method.

This cross-sectional study aimed to investigate the impact of metabolic-associated diseases (MADs) on patients with autoimmune hepatitis (AIH).

The study analyzed the clinical characteristics of 283 AIH patients who underwent liver biopsy between January 2016 and February 2022 in Ruijin Hospital, Shanghai, China.

Among the identified AIH patients (n = 283), 87.3%, 23.0%, or 43.1% had MADs, non-alcoholic fatty liver disease (NAFLD), or severe fibrosis, respectively. The proportion of diabetes mellitus (DM) was significantly higher in patients with severe liver fibrosis than in those with mild or moderate fibrosis in the AIH cohort (31.1% vs. 18.0%, p < 0.05). Fibrosis was also more severe in patients with NAFLD than in those without (53.8% vs. 39.9%, p < 0.05). Age, Plts, IgG and the presence with MADs were identified as independent predictors of the severity of inflammation in AIH patients. Moreover, severe liver fibrosis (stages 3 to 4) was independently associated with male (OR, 2.855; p = 0.025), γ-GT (OR, 0.997; p = 0.007), and combination with MADs (OR, 4.917; p = 0.006). Furthermore, combination with DM was also an independent predictor of severe liver fibrosis in AIH patients (OR, 2.445, p = 0.038).

Concurrent MADs, common in AIH patients, is an independent risk factor for severe fibrosis or inflammation; of note, combination with DM was also an independent predictor of severe liver fibrosis in AIH patients. While managing with AIH, routine assessment of co-existing MADs, especially DM, is also important.

Clinical trials in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis) require histologic scoring for assessment of inclusion criteria and endpoints. However, variability in interpretation has impacted clinical trial outcomes. We developed an artificial intelligence-based measurement (AIM) tool for scoring MASH histology (AIM-MASH). AIM-MASH predictions for MASH Clinical Research Network necroinflammation grades and fibrosis stages were reproducible (κ = 1) and aligned with expert pathologist consensus scores (κ = 0.62-0.74). The AIM-MASH versus consensus agreements were comparable to average pathologists for MASH Clinical Research Network scores (82% versus 81%) and fibrosis (97% versus 96%). Continuous scores produced by AIM-MASH for key histological features of MASH correlated with mean pathologist scores and noninvasive biomarkers and strongly predicted progression-free survival in patients with stage 3 (P < 0.0001) and stage 4 (P = 0.03) fibrosis. In a retrospective analysis of the ATLAS trial (NCT03449446), responders receiving study treatment showed a greater continuous change in fibrosis compared with placebo (P = 0.02). Overall, these results suggest that AIM-MASH may assist pathologists in histologic review of MASH clinical trials, reducing inter-rater variability on trial outcomes and offering a more sensitive and reproducible measure of patient responses.