Diagnostic accuracy of exhaled nitric oxide for the non-invasive identification of patients with fibrotic metabolic dysfunction-associated steatohepatitis.

BACKGROUND: Fibrotic metabolic dysfunction-associated steatohepatitis (MASH) is a condition at risk of progressing to advanced liver disease. We examined whether an innovative exhaled nitric oxide (eNO) breath test (BT) can accurately diagnose fibrotic MASH without requiring blood tests. METHODS: One hundred and forty-seven patients with MASH were recruited, and all tests were undertaken within 1 week of recruitment. With fibrotic MASH (NAS ≥ 4 and fibrosis stage ≥ 2) as the main outcome indicator, the diagnostic efficacy of eNO in identifying fibrotic MASH was compared to other validated models for advanced fibrosis requiring venesection, namely FAST, Agile 3+, and FIB-4 scores. RESULTS: The mean age was 40.36 ± 12.28 years, 73.5% were men. Mean body mass index was 28.83 ± 4.31 kg/m2. The proportion of fibrotic MASH was 29.25%. The area under the receiver operating curve for eNO in diagnosing fibrotic MASH was 0.737 [95% CI 0.650-0.823], which was comparable to FAST (0.751 [0.656-0.846]), Agile 3+ (0.764 [0.670-0.858]), and FIB-4 (0.721 [0.620-0.821]) (all DeLong test p > 0.05). A cut-off of eNO <8.5 ppb gave a sensitivity of 86.0% and a negative predictive value of 88.5% for ruling-out fibrotic MASH. A cut-off of eNO >13.5 ppb provided a specificity of 91.3% and a positive predictive value of 65.4% for ruling-in fibrotic MASH. Sensitivity analyses demonstrated that the diagnostic efficacy of eNO was similar across characteristics such as age. Moreover, adding vibration-controlled transient elastography-LSM (liver stiffness measurement) reduced the uncertainty interval from 46.9% to 39.5%. CONCLUSIONS: The eNO-BT is a promising simple test for non-invasively identifying fibrotic MASH, and its performance is further improved by adding LSM measurement.

[Clinical value of multiparameteric quantitative ultrasound for assessing high-risk steatohepatitis].

Objective: To investigate the clinical value of multiparameteric quantitative ultrasound combined with a non-invasive prediction model for assessing high-risk steatohepatitis. Methods: One hundred and ninety-four cases with metabolic-associated fatty liver disease (MAFLD) who underwent liver biopsy in Huashan Hospital, Fudan University, from June 2021 to September 2022 were selected. Shear wave elastography (SWE), shear wave dispersion (SWD) imaging, and attenuation imaging (ATI) examinations were conducted in all patients before biopsy. High-risk steatohepatitis was defined as a total activity score of ≥4 in patients with steatohepatitis, hepatocellular ballooning, and liver lobular inflammation based on pathological hepatic steatosis, inflammatory activity, and fibrosis scoring system (SAF), and fibrosis stage≥F2. Binary logistic regression analysis was used to identify the factors influencing high-risk steatohepatitis. A predictive model for diagnosing high-risk steatohepatitis was constructed using R language. The DeLong test was used to compare the area under the curve between groups. Measurement data was compared between groups using the t-test or rank-sum test, and count data were compared between groups using the χ2 test. Results: There were 46 cases (23.7%) with high-risk steatohepatitis. The quantitative ultrasound parameters included elastic modulus (OR=2.958, 95%CI: 1.889-4.883, P<0.001), dispersion coefficient (OR=1.786, 95%CI: 1.424-2.292, P<0.001) and attenuation coefficient (OR=42.642, 95%CI: 3.463-640.451, P=0.004). Serological indexes of fasting blood glucose (OR=1.196, 95%CI: 1.048-1.392, P=0.011), alanine aminotransferase (OR=1.012, 95%CI: 1.006-1.019, P<0.001), aspartate aminotransferase (OR=1.027, 95%CI: 1.014-1.042, P<0.001), γ-glutamyl transferase (OR=1.008, 95%CI: 1.001-1.017, P=0.041) and HDL cholesterol (OR=0.087, 95%CI: 0.016-0.404, P=0.003) were the factors influencing its progression. The AUCs of elastic modulus, dispersion coefficient, attenuation coefficient, multiparametric ultrasound model, serological index model, and ultrasound combined with serology model for the diagnosis of high-risk steatohepatitis were 0.764, 0.758, 0.634, 0.786, 0.773 and 0.825, respectively. The results of the DeLong test showed that the ultrasound combined with the serological model was significantly better than the serological index model and the elastic modulus, dispersion coefficient, and attenuation coefficient alone (P=0.024, 0.027, 0.038 and <0.001). Conclusion: The combination of multiparametric quantitative ultrasound is helpful for the non-invasive diagnosis of high-risk steatohepatitis and possesses great clinical significance.

Enhanced Artificial Intelligence Methods for Liver Steatosis Assessment Using Machine Learning and Color Image Processing: Liver Color Project.

BACKGROUND: The use of livers with significant steatosis is associated with worse transplantation outcomes. Brain death donor liver acceptance is mostly based on subjective surgeon assessment of liver appearance, since steatotic livers acquire a yellowish tone. The aim of this study was to develop a rapid, robust, accurate, and cost-effective method to assess liver steatosis. METHODS: From June 1, 2018, to November 30, 2023, photographs and tru-cut needle biopsies were taken from adult brain death donor livers at a single university hospital for the study. All the liver photographs were taken by smartphones then color calibrated, segmented, and divided into patches. Color and texture features were then extracted and used as input, and the machine learning method was applied. This is a collaborative project between Vall d'Hebron University Hospital and Barcelona MedTech, Pompeu Fabra University, and is referred to as LiverColor. RESULTS: A total of 192 livers (362 photographs and 7240 patches) were included. When setting a macrosteatosis threshold of 30%, the best results were obtained using the random forest classifier, achieving an AUROC = 0.74, with 85% accuracy. CONCLUSION: Machine learning coupled with liver texture and color analysis of photographs taken with smartphones provides excellent accuracy for determining liver steatosis.

Impact of gut microbiota on metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma: pathways, diagnostic opportunities and therapeutic advances.

Metabolic dysfunction-associated steatohepatitis (MASH) and progression to hepatocellular carcinoma (HCC) exhibits distinct molecular and immune characteristics. These traits are influenced by multiple factors, including the gut microbiome, which interacts with the liver through the "gut-liver axis". This bidirectional relationship between the gut and its microbiota and the liver plays a key role in driving various liver diseases, with microbial metabolites and immune responses being central to these processes. Our review consolidates the latest research on how gut microbiota contributes to MASH development and its progression to HCC, emphasizing new diagnostic and therapeutic possibilities. We performed a comprehensive literature review across PubMed/MedLine, Scopus, and Web of Science from January 2000 to August 2024, focusing on both preclinical and clinical studies that investigate the gut microbiota's roles in MASH and HCC. This includes research on pathogenesis, as well as diagnostic and therapeutic advancements related to the gut microbiota. This evidence emphasizes the critical role of the gut microbiome in the pathogenesis of MASH and HCC, highlighting the need for further clinical studies and trials. This is to refine diagnostic techniques and develop targeted therapies that exploit the microbiome's capabilities, aiming to enhance patient care in liver diseases.

Derivation and validation of the BIMAST score for predicting the presence of fibrosis due to Metabolic dysfunction-associated steatotic liver disease among diabetic patients in the community.

BACKGROUND & AIMS: Current screening pathways, developed from tertiary care cohorts, underestimate the presence of Metabolic-dysfunction associated steatotic liver disease (MASLD) in patients with type 2 diabetes mellitus (T2DM) in the community. We developed, validated, and assessed cost-effectiveness of a new score for screening the presence of fibrosis due to MASLD in primary care. METHODS: Consecutive T2DM patients underwent screening for liver diseases with transient elastography (TE). Based on predictors of significant/advanced fibrosis, we generated the BIMAST score (based on aspartate aminotransferase (AST) and body mass index (BMI)) and validated it internally and externally (Royal Free Hospital, London and Palermo Hospital). For cost-effectiveness analysis, 6 screening strategies were compared against standard of care: BIMAST score, ultrasound plus abnormal liver function tests, FIB-4, NAFLD fibrosis score, ELF and transient elastography (TE). A Markov model was built based on fibrosis status. Cost per quality-adjusted life year (QALY) gained and the incremental cost-effectiveness ratio (ICER) were estimated over a lifetime. RESULTS: Among 300 patients enrolled, 64% (186) had MASLD and 10% (28) other causes of liver disease. In the whole population, patients with significant fibrosis, advanced fibrosis, and cirrhosis due to MASLD were 17% (50/287), 11% (31/287), and 3% (8/287), respectively. In primary care, BIMAST performed better than other non-invasive markers at predicting significant and advanced fibrosis. Moreover, BIMAST reduced false negatives from 54% (ELF) and 38% (FIB-4) to 10%. In both validation cohorts, BIMAST performance was as good as FIB-4. In the cost-utility analysis, ICER was £2,337.92/QALY for BIMAST. CONCLUSION: The BIMAST predicts the presence of significant fibrosis in the community, reduces false negatives and is cost-effective. The BIMAST score should be included in the holistic assessment of diabetic patients.

The Clínica Universidad de Navarra-Body Adiposity Estimator index is a reliable tool for screening metabolic dysfunction-associated steatotic liver disease: an analysis from a gender perspective.

BACKGROUND: The Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE) Index, serves as an effective tool for evaluating body fat (BF) levels. This research seeks to clarify the association between the CUN-BAE Index and metabolic dysfunction-associated steatotic liver disease (MASLD) from a gender perspective. METHODS: The study utilized data from a comprehensive health assessment initiative known as "Human Dock", involving 14,251 participants. MASLD was diagnosed using abdominal ultrasound, primarily evaluated based on the following sonographic features: hepatorenal echo contrast, vascular blurring, deep attenuation, liver brightness. First, we evaluated the association of MASLD with the CUN-BAE Index using multivariate logistic regression. Second, we visualized this association and estimated potential threshold effect points using the restricted cubic spline (RCS) regression model. Ultimately, we evaluated the ability of the CUN-BAE Index to detect MASLD through receiver operating characteristic (ROC) curves. RESULTS: The female-to-male ratio was 1:1.08, with a MASLD prevalence rate of 17.59%. Following the adjustment for confounding variables, an increase of one unit in the CUN-BAE Index corresponded to a 14% increase in the risk of MASLD for males and an 18% increase for females. RCS analysis revealed an S-shaped relationship between MASLD prevalence and the CUN-BAE Index for both genders, with potential threshold effect points at approximately 30 in females and 15 in males. Beyond these threshold points, the prevalence of MASLD increased rapidly. Further subgroup analyses indicated significant differences in the relationship of the CUN-BAE Index with MASLD within age and body mass index (BMI) subgroups in females, with a stronger association observed in younger and non-obese female participants. Additionally, ROC analysis revealed that the CUN-BAE Index possesses a strong ability to distinguish MASLD in both genders, especially in females. CONCLUSIONS: This research is the first to identify a positive relationship between the CUN-BAE Index and MASLD. The CUN-BAE Index appears to be more suitable for early screening of MASLD in females.

Serum isthmin-1 is a potential biomarker for metabolic dysfunction associated fatty liver disease in patients with metabolic syndrome and type 2 diabetes mellitus.

INTRODUCTION: Metabolic dysfunction associated fatty liver disease (MAFLD) is a prevalent condition in patients with type 2 diabetes mellitus (T2DM). Isthmin-1 (ISM1) is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis. Although ISM1 has been shown to be associated with T2DM, its role in patients with MAFLD and metabolic syndrome (MetS) remains insufficiently examined. This study aimed to investigate the relationship between serum ISM1 and MAFLD in patients with T2DM and the potential involvement of MetS in this association. RESEARCH DESIGN AND METHODS: A total of 250 participants were divided into four groups: 60 patients with T2DM and MAFLD, 60 with newly diagnosed T2DM, 60 with MAFLD, and 70 healthy controls. Serum ISM1 levels were measured using ELISA. The distribution of ISM1 concentration in the combined data was divided into quartiles, and the Cochran-Armitage trend test was performed to estimate the significant trends across increasing quartiles. RESULTS: Compared with the controls, patients with coexisting MAFLD, MetS, and T2DM exhibited significantly elevated serum ISM1 concentrations. Serum ISM1 levels in the overweight/obese group were also higher than those in the lean group. Serum ISM1 levels were positively correlated with body mass index (BMI), uric acid, alanine aminotransferase, aspartate aminotransferase, total cholesterol (TC), low-density lipoprotein cholesterol, fasting insulin, and homeostasis model assessment of insulin resistance and negatively associated with age and high-density lipoprotein cholesterol (HDL-C). BMI, TC, and HDL-C were independently associated with serum ISM1 concentration. The relative risks for MAFLD, T2DM, and T2DM with MAFLD increased significantly with higher ISM1 quartiles. Furthermore, a positive correlation was observed between serum ISM1 levels and the number of MetS components, with the elevated plasma levels of ISM1 escalating the risk of developing MetS to some extent. CONCLUSIONS: The combination of ISM1 with TG and UA was identified as the best predictive factor for diagnosing MAFLD and MetS, potentially due to their contribution to aggravating the metabolic state.

[Elevated liver enzymes: update 2024]. / Élévation des tests hépatiques et maladies stéatosiques du foie : nouveautés 2024.

Elevated liver enzymes are a common finding in primary care medicine, with an estimated prevalence of 8 %. Steatotic liver diseases are the most frequently encountered etiologies and r-epresent the main cause of liver-related morbidity and mortality. This article looks at the latest developments in these diseases, with a particular focus on MASLD (Metabolic dysfunction associated steatotic liver disease). Recommendations include biological monitoring every 1-3 years in the presence of risk factors, and the use of the FIB-4 score to detect fibrosis in cases of MASLD. Therapeutic management aims to improve metabolic function by treating risk factors and through lifestyle and dietary measures.

La découverte d'une élévation des tests hépatiques est courante en médecine de premier recours, sa prévalence est estimée à 8 %. Les maladies hépatiques stéatosiques sont les étiologies les plus fréquemment retrouvées et représentent la principale cause de morbimortalité liée au foie. Cet article aborde les nouveautés concernant ces maladies et plus particulièrement la MASLD ou « Metabolic Dysfunction Associated Steatotic Liver Disease ¼. Les recommandations préconisent un suivi biologique tous les 1-3 ans en présence de facteurs de risque et l'utilisation du score FIB-4 (fibrosis-4) pour dépister la fibrose en cas de MASLD. La prise en charge thérapeutique vise à améliorer la dysfonction métabolique par des mesures hygiénodiététiques et le traitement des facteurs de risque.

Two-week continuous glucose monitoring-derived metrics and degree of hepatic steatosis: a cross-sectional study among Chinese middle-aged and elderly participants.

BACKGROUND: Continuous glucose monitoring (CGM) devices provide detailed information on daily glucose control and glycemic variability. Yet limited population-based studies have explored the association between CGM metrics and fatty liver. We aimed to investigate the associations of CGM metrics with the degree of hepatic steatosis. METHODS: This cross-sectional study included 1180 participants from the Guangzhou Nutrition and Health Study. CGM metrics, covering mean glucose level, glycemic variability, and in-range measures, were separately processed for all-day, nighttime, and daytime periods. Hepatic steatosis degree (healthy: n = 698; mild steatosis: n = 242; moderate/severe steatosis: n = 240) was determined by magnetic resonance imaging proton density fat fraction. Multivariate ordinal logistic regression models were conducted to estimate the associations between CGM metrics and steatosis degree. Machine learning models were employed to evaluate the predictive performance of CGM metrics for steatosis degree. RESULTS: Mean blood glucose, coefficient of variation (CV) of glucose, mean amplitude of glucose excursions (MAGE), and mean of daily differences (MODD) were positively associated with steatosis degree, with corresponding odds ratios (ORs) and 95% confidence intervals (CIs) of 1.35 (1.17, 1.56), 1.21 (1.06, 1.39), 1.37 (1.19, 1.57), and 1.35 (1.17, 1.56) during all-day period. Notably, lower daytime time in range (TIR) and higher nighttime TIR were associated with higher steatosis degree, with ORs (95% CIs) of 0.83 (0.73, 0.95) and 1.16 (1.00, 1.33), respectively. For moderate/severe steatosis (vs. healthy) prediction, the average area under the receiver operating characteristic curves were higher for the nighttime (0.69) and daytime (0.66) metrics than that of all-day metrics (0.63, P < 0.001 for all comparisons). The model combining both nighttime and daytime metrics achieved the highest predictive capacity (0.73), with nighttime MODD emerging as the most important predictor. CONCLUSIONS: Higher CGM-derived mean glucose and glycemic variability were linked with higher steatosis degree. CGM-derived metrics during nighttime and daytime provided distinct and complementary insights into hepatic steatosis.

Epicardial and liver fat implications in albuminuria: a retrospective study.

BACKGROUND: Albuminuria is considered an early and sensitive marker of kidney dysfunction, but also an independent cardiovascular risk factor. Considering the possible relationship among metabolic liver disease, cardiovascular disease and chronic kidney disease, we aimed to evaluate the risk of developing albuminuria regarding the presence of epicardial adipose tissue and the steatotic liver disease status. METHODS: A retrospective long-term longitudinal study including 181 patients was carried out. Epicardial adipose tissue and steatotic liver disease were assessed by computed tomography. The presence of albuminuria at follow-up was defined as the outcome. RESULTS: After a median follow up of 11.2 years, steatotic liver disease (HR 3.15; 95% CI, 1.20-8.26; p = 0.02) and excess amount of epicardial adipose tissue (HR 6.12; 95% CI, 1.69-22.19; p = 0.006) were associated with an increased risk of albuminuria after adjustment for visceral adipose tissue, sex, age, weight status, type 2 diabetes, prediabetes, hypertriglyceridemia, hypercholesterolemia, arterial hypertension, and cardiovascular prevention treatment at baseline. The presence of both conditions was associated with a higher risk of developing albuminuria compared to having steatotic liver disease alone (HR 5.91; 95% CI 1.15-30.41, p = 0.033). Compared with the first tertile of visceral adipose tissue, the proportion of subjects with liver steatosis and abnormal epicardial adipose tissue was significantly higher in the second and third tertile. We found a significant correlation between epicardial fat and steatotic liver disease (rho = 0.43 [p < 0.001]). CONCLUSIONS: Identification and management/decrease of excess adiposity must be a target in the primary and secondary prevention of chronic kidney disease development and progression. Visceral adiposity assessment may be an adequate target in the daily clinical setting. Moreover, epicardial adipose tissue and steatotic liver disease assessment may aid in the primary prevention of renal dysfunction.

Assessment of the clinical value of five noninvasive predictors of metabolic dysfunction-associated steatotic liver disease in Han Chinese adults.

BACKGROUND: Fatty Liver Index (FLI), Triglyceride-Glucose Index (TyG), Lipid Accumulation Product (LAP), Zhejiang University Index (ZJU), and Visceral Adiposity Index (VAI) are five classical predictive models for fatty liver disease. Our cross-sectional study aimed to identify the optimal predictors by comparing the predictive value of five models for metabolic dysfunction-associated steatotic liver disease (MASLD) risk. METHODS: Data on 2687 participants were collected from West China Hospital of Sichuan University. Controlled attenuation parameters assessed by transient elastography were used to effectively diagnose MASLD. Logistic regression analysis was used to estimate the odd ratios and 95% confidence intervals between indices and MASLD risk. Receiver operating characteristic curves were plotted to evaluate the predictive value of indices. RESULTS: This study included 1337 normal and 1350 MASLD samples. The average age of MASLD patients is 47 years old, and the prevalence was higher in males (39.3%) than in females (10.9%). Five indices were positively correlated with MASLD risk, with the strongest correlation for TyG. Overall, the area under the curve of the indicators was: ZJU 0.988, FLI 0.987, LAP 0.982, TyG 0.942, and VAI 0.941. In the gender stratification, ZJU (0.989) performed best in males. FLI (0.988) and ZJU (0.987) had similar predictive ability in females. In the age stratification, FLI performed better in predicting the middle-aged group aged 30-40 years (0.991). CONCLUSION: For Chinese Han adults, ZJU is the best predictive index for initial screening of MASLD. FLI can serve as an alternative tool for ZJU to predict females.

LIVERSTAT for risk stratification for patients with metabolic dysfunction-associated fatty liver disease.

BACKGROUND AND AIM: LIVERSTAT is an artificial intelligence-based noninvasive test devised to screen for and provide risk stratification for metabolic dysfunction-associated fatty liver disease (MAFLD) by using simple blood biomarkers and anthropometric measurements. We aimed to study LIVERSTAT in patients with MAFLD and to explore its role for the diagnosis of advanced fibrosis. METHODS: This is a retrospective study of data from MAFLD patients who underwent a liver biopsy. Patients with type 2 diabetes who underwent transient elastography and had liver stiffness measurement (LSM) < 5 kPa were included as patients with no fibrosis. Among these patients, controlled attenuation parameter <248 dB/m was considered as no steatosis. The LIVERSTAT results were generated based on a proprietary algorithm, blinded to the histological and LSM data. RESULTS: The data for 350 patients were analyzed (mean age 53 years, 45% male, advanced fibrosis 22%). The sensitivity, specificity, positive predictive value, negative predictive value, and misclassification rate of LIVERSTAT to diagnose advanced fibrosis were 90%, 50%, 30%, 95%, and 42%, respectively. The corresponding rates for Fibrosis-4 score (FIB4) were 56%, 83%, 44%, 89%, and 22%, respectively. When LSM was used as a second test, the corresponding rates for LIVERSTAT were 60%, 97%, 76%, 94%, and 8%, respectively, while the corresponding rates for FIB4 were 38%, 99%, 83%, 89%, and 11%, respectively. CONCLUSION: LIVERSTAT had a higher negative predictive value compared with FIB4 and a lower misclassification rate compared with FIB4 when used in a two-step approach in combination with LSM for the diagnosis of advanced fibrosis.

Serum-free light chains as a dependable biomarker for stratifying patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: Adaptive immunity is gaining a significant role in progression of metabolic dysfunction-associated steatotic liver disease (MASLD). B-cell activity can be assessed by serum-free light chains (sFLCs) k and λ levels. The objective of the present investigation is to examine the utility of sFLCs as non-invasive biomarkers for the stratification of MASLD. METHODS: We enrolled a consecutive cohort from an outpatient liver unit. Diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) was made with liver biopsy according to current guidelines. Compensated advanced chronic liver disease (cACLD) and clinically significant portal hypertension (CSPH) were defined according to Baveno VII criteria. sFLCs were measured by turbidimetry using an immunoassay. RESULTS: We evaluated 254 patients, 162/254 (63.8%) were male. Median age was 54 years old, and the median body mass index was 28.4 kg/m2. A total of 157/254 (61.8%) subjects underwent liver biopsy: 88 had histological diagnosis of MASH, 89 were considered as simple metabolic dysfunction-associated steatotic liver (MASL) and 77/254 (30.3%) patients with compensated metabolic dysfunction-associated cirrhosis. By using Baveno VII criteria, 101/254 (39.7%) patients had cACLD; among them, 45/101 (44.5%) had CSPH. Patients with cACLD showed higher sFLC levels compared with patients without cACLD (p < .01), and patients with CSPH showed higher sFLC levels than patients without CSPH (p < .01). At multivariable analysis, sFLCs were associated with cACLD (p < .05) independently from γ-globulins and other known dysmetabolic risk factors. κFLC was associated with CSPH (p < .05) independently from γ-globulins and other known dysmetabolic risk factors. CONCLUSION: sFLCs could be a simple biomarker for stratification of cACLD in MASLD patients.

Epidemiology and diagnosis of metabolic dysfunction-associated fatty liver disease.

The most common chronic liver illness worldwide is metabolic dysfunction linked to fatty liver disease (MAFLD), which is poorly understood by doctors and patients. Many people with this disease develop steatohepatitis, cirrhosis and its consequences, as well as extrahepatic manifestations; these conditions are particularly common if they are linked to diabetes mellitus or obesity. A breakthrough with numerous benefits is the switch from NAFLD to MAFLD in terms of terminology and methodology. The diagnosis of MAFLD is based on affirmative criteria; unlike NAFLD, it is no longer based on exclusion. The diagnosis of MAFLD and the evaluation of steatosis and fibrosis is achieved using liver biopsy and non-invasive laboratory or radiographic techniques. We briefly address the most recent developments in MAFLD epidemiology and diagnosis.

Alanine aminotransferase predicts incident steatotic liver disease of metabolic etiology: Long life to the old biomarker!

Alanine aminotransferase (ALT) serum levels increase because of hepatocellular damage. Metabolic dysfunction-associated fatty liver disease (MAFLD), which identifies steatotic liver disease (SLD) associated with ≥ 2 metabolic abnormalities, has prominent sexual differences. The Metabolic Syndrome defines a cluster comprising abdominal obesity, altered glucose metabolism, dyslipidemia, and hypertension. Male sex, body mass index, glucose, lipids, ferritin, hypertension, and age independently predict ALT levels among blood donors. Over the last few decades, the reference range of ALT levels has been animatedly debated owing to attempts to update sex-specific reference ranges. With this backset, Chen et al have recently published a study which has two main findings. First, > 80% of individuals with MAFLD had normal ALT levels. Second, there was a linear increasing trend in the association between cumulative excess high-normal ALT levels and the rate of incident MAFLD. This study has biologically credible findings. However, it inaccurately considered sex differences in the MAFLD arena. Therefore, future studies on SLD owing to metabolic dysfunction should adopt locally determined and prospectively validated reference ranges of ALT and carefully consider sex differences in liver enzymes and MAFLD pathobiology.

Swept up in the tsunami: Pediatric and adolescent steatotic (fatty) liver disease.

The worldwide epidemic of steatotic (fatty) liver disease also affects children and adolescents. The consensus statement by Zhang et al.1 summarizes key evidence on detection, risk factors, manifestations, comorbidities, and potential treatments in children and adolescents. The work emphasizes the need for advancements in managing this threat to the health and longevity of young individuals.

Fetuin-A: a relevant novel serum biomarker for non-invasive diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD): a retrospective case-control study.

OBJECTIVES: To determine how fetuin-A contributes to diagnosing and assessing MASLD severity. METHODS: Fifty MASLD patients and fifty healthy control participants were involved in this retrospective case-control research. Abdominal ultrasonography, fibroscan with controlled attenuated parameter scan (CAP scan), laboratory investigation (including fetuin-A assessment), clinical examination, and history-taking were performed on every case. RESULTS: Fetuin-A level was considerably higher in the Cases group (1154.85 ± 629.89) than in the Control group (505.29 ± 150.4) (p < 0.001). Fetuin-A had significant validity in the prediction of MASLD at a cut-off > 702.5 with 82% sensitivity, 90% specificity, and 86% overall accuracy. CONCLUSION: One possible marker for MASLD diagnosis could be fetuin-A. Furthermore, a substantial association between such marker and the severity of the disease as it revealed a significant correlation with ultrasound grading and fibroscan with controlled attenuated parameters. Trial registration 1- Pan African Clinical Trial Registry. Unique Identifying number/registration ID: PACTR202309644280965. URL: https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=26860 . Registration Approval date: 21/09/2023. 2- ClinicalTrials.gov. Unique Identifying number /registration ID: NCT06097039. URL: https://clinicaltrials.gov/study/NCT06097039?cond=NCT06097039&rank=1 . Registration Approval date: 25/10/2023.

Gut microbiota-based machine-learning signature for the diagnosis of alcohol-associated and metabolic dysfunction-associated steatotic liver disease.

Alcoholic-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD) show a high prevalence rate worldwide. As gut microbiota represents current state of ALD and MASLD via gut-liver axis, typical characteristics of gut microbiota can be used as a potential diagnostic marker in ALD and MASLD. Machine learning (ML) algorithms improve diagnostic performance in various diseases. Using gut microbiota-based ML algorithms, we evaluated the diagnostic index for ALD and MASLD. Fecal 16S rRNA sequencing data of 263 ALD (control, elevated liver enzyme [ELE], cirrhosis, and hepatocellular carcinoma [HCC]) and 201 MASLD (control and ELE) subjects were collected. For external validation, 126 ALD and 84 MASLD subjects were recruited. Four supervised ML algorithms (support vector machine, random forest, multilevel perceptron, and convolutional neural network) were used for classification with 20, 40, 60, and 80 features, in which three nonsupervised ML algorithms (independent component analysis, principal component analysis, linear discriminant analysis, and random projection) were used for feature reduction. A total of 52 combinations of ML algorithms for each pair of subgroups were performed with 60 hyperparameter variations and Stratified ShuffleSplit tenfold cross validation. The ML models of the convolutional neural network combined with principal component analysis achieved areas under the receiver operating characteristic curve (AUCs) > 0.90. In ALD, the diagnostic AUC values of the ML strategy (vs. control) were 0.94, 0.97, and 0.96 for ELE, cirrhosis, and liver cancer, respectively. The AUC value (vs. control) for MASLD (ELE) was 0.93. In the external validation, the AUC values of ALD and MASLD (vs control) were > 0.90 and 0.88, respectively. The gut microbiota-based ML strategy can be used for the diagnosis of ALD and MASLD.ClinicalTrials.gov NCT04339725.

Performance of novel collagen turnover biomarkers to detect increased liver stiffness in MASLD.

BACKGROUND: Cleavage products from collagen formation and degradation hold potential as first-line biomarkers for the risk of advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we evaluated the performance of PRO-C3, PRO-C6, C4M, PRO-C18L, and the clinical score ADAPT (age, diabetes, PRO-C3, and platelet count) to detect patients with an LSM >8 kPa or >12 kPa in comparison to the Fibrosis-4 Index (FIB-4). METHODS: Serum from patients with MASLD (n = 269) from six Swedish University Hospitals was analyzed using enzyme-linked immunosorbent assay-based methods. Liver stiffness measurement (LSM) by vibration-controlled transient elastography was performed. The area under the curve (AUC), calibration curves, and net benefit analysis were used. RESULTS: An LSM >8 kPa was found in 108 (40.1%) patients. PRO-C3, PRO-C6, C4M, and PRO-C18L had AUCs ranging from 0.48 to 0.62. ADAPT had the highest AUC (0.73, 95% confidence interval [CI] = 0.67-0.79) to detect patients >8 kPa, compared to FIB-4 (0.71, (95%CI = 0.64-0.77, p = 0.35), and had a higher net benefit compared to FIB-4 from a probability threshold of 15%. FIB-4 and ADAPT performed equally well to detect patients with an LSM >12 kPa, AUC 0.76 versus 0.76, p = 0.93. CONCLUSIONS: ADAPT seems to be marginally better than FIB-4 in identifying patients with an LSM >8 kPa. However, the clinical utility of ADAPT as a first line test is uncertain, especially in low-risk populations. The overall performance of FIB-4 was similar to that of ADAPT in detecting patients with an LSM of >12 kPa. Altogether, the results suggest that ADAPT might be useful to detect earlier stages of fibrosis in MASLD, but that FIB-4 remains a first-line test for advanced fibrosis.