Hepatic venous pressure gradient predicts risk of hepatic decompensation and liver-related mortality in patients with MASLD.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of advanced chronic liver disease (ACLD). Portal hypertension drives hepatic decompensation and is best diagnosed by hepatic venous pressure gradient (HVPG) measurement. Here we investigate the prognostic value of HVPG in compensated (cACLD) MASLD. METHODS: This European multicentre study included MASLD-cACLD patients characterised by HVPG at baseline. Hepatic decompensation (variceal bleeding/ ascites/hepatic encephalopathy) and liver-related mortality were considered the primary events of interest. RESULTS: 340 MASLD-cACLD patients [56.2% men; age: 62 (55-68) years; MELD: 8 (7-9); 71.2% diabetes] were included. Clinically significant portal hypertension (CSPH; i.e., HVPG ≥10 mmHg) was found in 209 patients (61.5%). During a median follow-up of 41.5 (27.5-65.8) months, 65 patients developed hepatic decompensation with a cumulative incidence of 10.0% after 2 years (2Y) and 30.7% after 5 years (5Y) in MASLD-cACLD with CSPH, compared to 2.4% after 2Y and 9.4% after 5Y in patients without CSPH. Variceal bleeding did not occur without CSPH. CSPH (subdistribution hazard ratio, SHR:5.13; p<0.001) was associated with an increased decompensation risk and a higher HVPG remained an independent risk factor in the multivariable model (aSHR per mmHg:1.12; p<0.001). Liver-related mortality occurred in 37 patients with a cumulative incidence of 3.3% after 2Y and 21.4% after 5Y in CSPH. Without CSPH, the incidence after 5Y was 0.8%. Accordingly, a higher HVPG was also independently associated with a higher risk of liver-related death (aSHR per mmHg:1.20; p<0.001). CONCLUSION: HVPG measurement is of high prognostic value in MASLD-cACLD. While MASLD-cACLD patients without CSPH show a very low short-term risk of decompensation and liver-related mortality is rare, the presence of CSPH substantially increases both risks. IMPACT AND IMPLICATIONS: While the incidence of compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide, insights into the impact of clinically significant portal hypertension (CSPH) on the risk of liver-related events in MASLD-cACLD remain limited. Based on the findings of this European multicentre study including 340 MASLD-cACLD, we could show that increasing HVPG values and the presence of CSPH in particular were associated with a significantly higher risk of first hepatic decompensation and liver-related mortality. In contrast, the short-term incidence of decompensation in MASLD-cACLD patients without CSPH was low and the risk of liver-mortality remained negligible. Thus, HVPG measurements can provide important prognostic information for individualised risk-stratification in MASLD-cACLD and may help facilitate the study of novel and promising treatment possibilities for MASLD.

Phenotypes of Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) typically develops as a consequence of liver cirrhosis, but HCC epidemiology has evolved drastically in recent years. Metabolic dysfunction-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis, has emerged as the most common chronic liver disease worldwide and a leading cause of HCC. A substantial proportion of MASLD-associated HCC (MASLD-HCC) also can develop in patients without cirrhosis. The specific pathways that trigger carcinogenesis in this context are not elucidated completely, and recommendations for HCC surveillance in MASLD patients are challenging. In the era of precision medicine, it is critical to understand the processes that define the profiles of patients at increased risk of HCC in the MASLD setting, including cardiometabolic risk factors and the molecular targets that could be tackled effectively. Ideally, defining categories that encompass key pathophysiological features, associated with tailored diagnostic and treatment strategies, should facilitate the identification of specific MASLD-HCC phenotypes. In this review, we discuss MASLD-HCC, including its epidemiology and health care burden, the mechanistic data promoting MASLD, metabolic dysfunction-associated steatohepatitis, and MASLD-HCC. Its natural history, prognosis, and treatment are addressed specifically, as the role of metabolic phenotypes of MASLD-HCC as a potential strategy for risk stratification. The challenges in identifying high-risk patients and screening strategies also are discussed, as well as the potential approaches for MASLD-HCC prevention and treatment.

Which Educational Topics and Smartphone App Functions Are Prioritized by US Patients With Rheumatic and Musculoskeletal Diseases? A Mixed-Methods Study.

OBJECTIVE: We sought to identify (1) what types of information US adults with rheumatic and musculoskeletal diseases (RMD) perceive as most important to know about their disease, and (2) what functions they would use in an RMD-specific smartphone app. METHODS: Nominal groups with patients with RMD were conducted using online tools to generate a list of needed educational topics. Based on nominal group results, a survey with final educational items was administered online, along with questions about desired functions of a smartphone app for RMD and wearable use, to patients within a large community rheumatology practice-based research network and the PatientSpot registry. Chi-square tests and multivariate regression models were used to determine differences in priorities between groups of respondents with rheumatic inflammatory conditions (RICs) and osteoarthritis (OA), and possible associations. RESULTS: At least 80% of respondents considered finding a rheumatologist, understanding tests and medications, and quickly recognizing and communicating symptoms to doctors as extremely important educational topics. The highest-ranked topic for both RIC and OA groups was "knowing when the medication is not working." The app functions that most respondents considered useful were viewing laboratory results, recording symptoms to share with their rheumatology provider, and recording symptoms (eg, pain, fatigue) or disease flares for health tracking over time. Approximately one-third of respondents owned and regularly used a wearable activity tracker. CONCLUSION: People with RMD prioritized information about laboratory test results, medications, and disease and symptom monitoring, which can be used to create educational and digital tools that support patients during their disease journey.

Are language-cognition interactions bigger than a breadbox? Integrative modeling and design space thinking temper simplistic questions about causally dense phenomena.

We affirm the utility of integrative modeling, according to which it is advantageous to move beyond "one-at-a-time binary paradigms" through studies that position themselves within realistic multidimensional design spaces. We extend the integrative modeling approach to a target domain with which we are familiar, the consequences of bilingualism on mind and brain, often referred to as the "bilingual advantage." In doing so, we highlight work from our group consistent with integrative modeling.

Point-of-Care Noninvasive Prediction of Liver-Related Events in Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Individual risk prediction of liver-related events (LRE) is needed for clinical assessment of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) patients. We aimed to provide point-of-care validated liver stiffness measurement (LSM)-based risk prediction models for the development of LRE in patients with NAFLD, focusing on selecting patients for clinical trials at risk of clinical events. METHODS: Two large multicenter cohorts were evaluated, 2638 NAFLD patients covering all LSM values as the derivation cohort and 679 more advanced patients as the validation cohort. We used Cox regression to develop and validate risk prediction models based on LSM alone, and the ANTICIPATE and ANTICIPATE-NASH models for clinically significant portal hypertension. The main outcome of the study was the rate of LRE in the first 3 years after initial assessment. RESULTS: The 3 predictive models had similar performance in the derivation cohort with a very high discriminative value (c-statistic, 0.87-0.91). In the validation cohort, the LSM-LRE alone model had a significant inferior discrimination (c-statistic, 0.75) compared with the other 2 models, whereas the ANTICIPATE-NASH-LRE model (0.81) was significantly better than the ANTICIPATE-LRE model (0.79). In addition, the ANTICIPATE-NASH-LRE model presented very good calibration in the validation cohort (integrated calibration index, 0.016), and was better than the ANTICIPATE-LRE model. CONCLUSIONS: The ANTICIPATE-LRE models, and especially the ANTICIPATE-NASH-LRE model, could be valuable validated clinical tools to individually assess the risk of LRE at 3 years in patients with NAFLD/NASH.

Enterohepatic Shunt-Driven Cholemia Predisposes to Liver Cancer.

BACKGROUND & AIMS: Pathogenesis of hepatocellular carcinoma (HCC), which kills millions annually, is poorly understood. Identification of risk factors and modifiable determinants and mechanistic understanding of how they impact HCC are urgently needed. METHODS: We sought early prognostic indicators of HCC in C57BL/6 mice, which we found were prone to developing this disease when fed a fermentable fiber-enriched diet. Such markers were used to phenotype and interrogate stages of HCC development. Their human relevance was tested using serum collected prospectively from an HCC/case-control cohort. RESULTS: HCC proneness in mice was dictated by the presence of congenitally present portosystemic shunt (PSS), which resulted in markedly elevated serum bile acids (BAs). Approximately 10% of mice from various sources exhibited PSS/cholemia, but lacked an overt phenotype when fed standard chow. However, PSS/cholemic mice fed compositionally defined diets, developed BA- and cyclooxygenase-dependent liver injury, which was exacerbated and uniformly progressed to HCC when diets were enriched with the fermentable fiber inulin. Such progression to cholestatic HCC associated with exacerbated cholemia and an immunosuppressive milieu, both of which were required in that HCC was prevented by impeding BA biosynthesis or neutralizing interleukin-10 or programmed death protein 1. Analysis of human sera revealed that elevated BA was associated with future development of HCC. CONCLUSIONS: PSS is relatively common in C57BL/6 mice and causes silent cholemia, which predisposes to liver injury and HCC, particularly when fed a fermentable fiber-enriched diet. Incidence of silent PSS/cholemia in humans awaits investigation. Regardless, measuring serum BA may aid HCC risk assessment, potentially alerting select individuals to consider dietary or BA interventions.

Effects of Smoking Marijuana on the Respiratory System: A Systematic Review.

BACKGROUND: The prevalence of marijuana use and its derivatives has surged over the past century, largely due to increasing legalization globally. Despite arguments advocating its benefits, marijuana smoking exposes the lungs to harmful combustion byproducts, leading to various respiratory issues such as asthma, pneumonia, emphysema, and chronic obstructive pulmonary disease. METHODS: We embarked on an extensive literature search, utilizing PubMed/Medline, Scopus, Web of Science, and Google Scholar databases, identifying 200 studies. After the elimination of duplicates, and meticulous review of abstracts and full texts, 55 studies were included in our analysis. RESULTS: Current literature demonstrates that marijuana use negatively impacts lung function, triggering symptoms like chronic cough, sputum production, and wheezing, and diminishing FEV1/FVC ratio in spirometry tests. Moreover, prolonged or chronic marijuana use augments the risk of respiratory function impairment. While the carcinogenic effects of marijuana are still contested, a weak correlation between marijuana use and lung cancer has been observed in some studies. Additionally, instances of other pathologies linked to marijuana use have been reported, including the development of COPD, pulmonary bullae, spontaneous pneumothorax, pleuritic pain, chronic pulmonary aspergillosis, hemoptysis, and pulmonary Langerhans cell histiocytosis. CONCLUSIONS: The evidence underscores that marijuana use is detrimental to respiratory health. In light of the escalating trend of marijuana use, particularly among the youth, it is imperative to advocate public health messages discouraging its consumption.

Weil syndrome coincident with upper gastrointestinal bleeding.

A 48 year old male was referred to our center due to a gastrointestinal bleeding with melena secondary to a Forrest IIb gastric ulcer treated endoscopically. Physical examination revealed bilateral conjunctival suffusion, bradypsychia, and asterixis. Epidemiological history included a trip to Dominican Republic two weeks before, presenting later a flu-like syndrome. He had no history of NSAID use. Laboratory tests showed a normocytic anemia, leukocytosis with neutrophilia, acute renal failure, severe hyponatremia, a predominant direct hyperbilirubinemia, hyperamylasemia, and mild coagulopathy (Table 1). An abdominal ultrasound was performed, with no pathological findings, and a chest-abdominal computed tomography (CT), bilateral diffuse ground glass pulmonary opacities and pleural effusion, mild hepatomegaly, and peritoneal and gastrohepatic ligament lymphadenopathy, with no signs of acute pancreatitis. A second look upper endoscopy revealed a Forrest III gastric ulcer. Gastric biopsies results ruled out malignancy and Helicobacter pylori infection. Due to his recent travel history combined with his characteristic signs and symptoms a clinical diagnosis of leptospirosis was made and empirical antibiotic therapy with meropenem was started. The serology for Leptospira was positive (IgG 1/1600) and antibiotic therapy was de-escalated to ceftriaxone with clinical and analytical remission on day five of his hospital stay with complete radiological resolution at 6 months.

Prediction of clinical events by liver stiffness and chronic kidney disease by NAFLD in patients with type-2 diabetes.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with poorer glycemic control and a higher risk of type-2 diabetes (T2D) complications, extrahepatic and cardiovascular disease (CVD). Our study aim was to evaluate the association between NAFLD, T2D complications, and the development of overall clinical events (OCE) (CV, liver-related, and mortality) in patients with T2D. METHODS: Prospective single-center study comprising T2D subjects with no history of CVD and non-T2D matched controls. Patients were selected from the Outpatient Diabetes Clinic of Vall d'Hebron Hospital and related primary care centers. RESULTS: 186 diabetics and 57 controls were included. Amongst T2D, 124/186 subjects had NAFLD (66.6%). T2D-NAFLD subjects showed a heavier metabolic burden and higher median liver stiffness (5.6kPa [4.5-7.3] vs 4.8 [4.2-5.8]; p=0.004) compared to non-NAFLD diabetics. During a median follow-up of 5.6 years, 33 (17.7%) T2D patients developed OCE vs 4 (7.0%) controls (p=0.049). No differences were found for OCE between NAFLD and non-NAFLD diabetics (16.9% vs 19.4%; p=0.68). CV was the most reported outcome and only one liver event occurred. NAFLD diabetics showed more often chronic kidney disease (CKD), whereas T2D complications and subclinical CVD rates were similar. A higher liver stiffness, older age, and male gender were independently associated with OCE amongst the entire T2D population and NAFLD diabetics. CONCLUSIONS: NAFLD and liver stiffness were associated with CKD and clinical outcomes in diabetics, respectively. A hepatic evaluation is recommended to identify high-risk T2D patients that would benefit from early referral to specialized care.

[Metabolic morbidity in the prison population of Catalonia, Spain]. / Morbilidad metabólica en la población penitenciaria de Cataluña.

OBJECTIVE: To investigate the prevalence of metabolic morbidity (MM) amongst prison inmates. DESIGN: Multicentric, cross-sectional observational study. SETTING: All (nine) prisons in Catalonia. PARTICIPANTS: Convicted inmates that are not in an «open regime¼, whose healthcare relies on the Prison Primary Care Teams. INTERVENTIONS: MM was defined as the presence of at least one component of the metabolic syndrome, i.e., obesity, arterial hypertension, type2 diabetes, and/or dyslipidemia. The variables collected included anthropometric measurements, medical history and laboratory values related to MM. The source of information was the Catalan Primary Healthcare Services Information System (SISAP). MAIN MEASUREMENTS: The prevalence of MM, overall and by several participant subcategories, was calculated. To investigate the risk factors associated to a higher prevalence of MM, a multivariable logistic regression analysis was carried out and expressed as adjusted odds ratios and 95% confidence intervals. RESULTS: 4338 inmates were studied, of whom 93.9% were male. Mean age was 38.4years, 51.7% were born in European Union countries, and 6.7% were infected by HIV. The variables associated with a significantly increased risk of presenting MM were older age and HIV infection, whereas certain geographical origins (i.e., non-UE European countries, Maghreb and Sub-Saharan Africa) were associated with lower risk of MM. CONCLUSIONS: In spite of being an overall young population, prison inmates present high rates of MM. Older age, HIV infection and geographic origin appear as the most strongly associated factors with MM in the prison population. MM should be detected early in order to prevent complications. Prevention, screening and treatment of MM ought to be considered a priority in the clinical routine of prison healthcare professionals.

Prevalence estimation of significant fibrosis because of NASH in Spain combining transient elastography and histology.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has become a major public health problem, but the prevalence of fibrosis associated with non-alcoholic steatohepatitis (NASH) is largely unknown in the general population. This study aimed to provide an updated estimation of the prevalence of NASH fibrosis in Spain. METHODS: This was an observational, retrospective, cross-sectional, population-based study with merged data from two Spanish datasets: a large (N = 12 246) population-based cohort (ETHON), including transient elastography (TE) data, and a contemporary multi-centric biopsy-proven NASH cohort with paired TE data from tertiary centres (N = 501). Prevalence for each NASH fibrosis stage was estimated by crossing TE data from ETHON dataset with histology data from the biopsy-proven cohort. RESULTS: From the patients with valid TE in ETHON dataset (N = 11 440), 5.61% (95% confidence interval [95% CI]: 2.53-11.97) had a liver stiffness measurement (LSM) ≥ 8 kPa. The proportion attributable to NAFLD (using clinical variables and Controlled Attenuation Parameter) was 57.3% and thus, the estimated prevalence of population with LSM ≥ 8 kPa because of NAFLD was 3.21% (95% CI 1.13-8.75). In the biopsy-proven NASH cohort, 389 patients had LSM ≥ 8 kPa. Among these, 37% did not have significant fibrosis (F2-4). The estimated prevalence of NASH F2-3 and cirrhosis in Spain's adult population were 1.33% (95% CI 0.29-5.98) and 0.70% (95% CI 0.10-4.95) respectively. CONCLUSIONS: These estimations provide an accurate picture of the current prevalence of NASH-related fibrosis in Spain and can serve as reference point for dimensioning the therapeutic efforts that will be required as NASH therapies become available.

Accessibility of adult immunizations in pharmacies compared to physician offices in low-income communities.

BACKGROUND: Expanding access to immunization services is essential for improving low-income communities' access to health care. OBJECTIVE: The purpose of this analysis was to assess whether adults who live in low-income communities, and adults 65 years old and older who live in low-income communities, have greater access to pharmacies for immunization services than to relevant physician offices. METHODS: Databases of the number of physician practices and pharmacy locations were geocoded into ZIP Code tabulation areas (ZCTAs). The ZCTAs where the share of families living at or below the federal poverty threshold exceeded 30% were defined as low-income communities for purposes of the analysis. The raw access comparisons were adjusted to reflect whether physician practices have Medicare Part D billing capability, an access constraint for patients aged 65 years and over, and to reflect the differences in hours of operation. RESULTS: There were 15.1% more pharmacy locations within the low-income communities than the availability of physician practices. After adjusting for the hours of operation, the pharmacy locations offered 95.7% more operating hours than the physician practice sites. Compared to the physician practices that have Medicare Part D billing capability, there were 203.0% more pharmacy locations. CONCLUSION: Based on the results, lower-income families had greater access to pharmacies than to physician practices, which indicates that pharmacies can play a valuable role in expanding immunization access and could warrant considering policy reforms that enhance the authority of pharmacists to administer vaccinations. State-level potential reforms could include expanding and harmonizing laws governing pharmacist authority to deliver such services, creating health enterprise zones, and granting special tax breaks, regulatory exemptions, or public assistance to encourage the establishment of physician offices and pharmacies in low-income communities.

Outcomes and potential surrogate markers for future clinical trials of non-alcoholic steatohepatitis cirrhosis.

Non-alcoholic steatohepatitis has emerged as a major public health problem, and the burden of non-alcoholic steatohepatitis cirrhosis is projected to increase by 64%-156% by 2030. The threat is aggravated by the fact that are currently no approved drugs for the treatment of non-alcoholic steatohepatitis. In this paper, we review the main challenges to drug development in patients with non-alcoholic steatohepatitis cirrhosis, and describe the opportunities brought by the advances in the understanding of the clinical and pathophysiological nuances of cirrhosis. The design of therapeutic regimens for non-alcoholic steatohepatitis cirrhosis will vary according to the specific cirrhosis substage (compensated vs decompensated), and the specific mechanistic basis of therapy, targeted either at improving aetiology-specific pathways and/or at more general aetiology-agnostic processes. The understanding of the probabilistic expectations for the whole range of potential outcomes, rooted at different mechanistic drivers at each specific substage, will be essential in order to choose adequate estimands and therapeutic strategies for clinical trials and individual patients with non-alcoholic steatohepatitis cirrhosis. Finally, we provide a summary of the main pitfalls and uncertainties in the design of clinical trials for non-alcoholic steatohepatitis cirrhosis and discuss potential biomarkers for use in trials and practice for these patients.

'Spending all this time stressing and worrying and calculating': marginal food security and student life at a Diverse Urban University.

OBJECTIVE: Food security status is a continuum ranging from high to very low food security. While marginal food security falls next to high food security on the spectrum, new quantitative research indicates marginal food security status is associated with negative health outcomes and poor academic performance among college students. Qualitative research focusing on college students experiencing marginal food security has not been conducted. The current study aims to qualitatively explore experiences of college students with marginal food security and to identify themes to better understand and provide context regarding how marginal food security impacts students. DESIGN: Students were recruited for semi-structured interviews with questions designed to study the challenges associated with students' food situations. All interviews were recorded and transcribed with themes identified via an inductive approach. SETTING: A large public university on the US west coast. PARTICIPANTS: Thirty college students. RESULTS: Key themes that emerged: purchasing cheap unhealthy foods, insufficient time to prepare and eat meals on a regular basis, stress and anxiety around the inability to eat healthy food and future health issues, self-perception of health when eating poorly along with physical symptoms and low academic motivation by not fully participating in their courses due to few healthy food options or missing meals. CONCLUSION: Marginal food security can potentially diminish students' health and their capacity to learn and succeed in their coursework. The results emphasise that students experiencing marginal food security should not be grouped with students experiencing high food security.

Thermoluminescence from Cu Doped Lithium Tetraborate Irradiated with X-ray and γ Using 137Cs Radioactive Source.

Lithium tetraborate (Li2B4O7) pellets prepared by using water/solution assisted method were synthesized and characterized. Copper was used as doping material in order to enhance the Li2B4O7 thermoluminescent properties. For synthesis heating temperature parameters were defined at 750 °C for 2 hr, followed by 150 °C for another 2 hr. The materials were produced at five different Cu concentrations: 0.02, 0.04, 0.06, 0.08, and 0.1 wt%. The luminescent and morphological characterizations were performed by X-ray diffraction (XRD), Scanning electron microscope (SEM), Photoluminescence (PL), and Ultraviolet-visible spectroscopy (UV-Vis). XRD and SEM analysis of intrinsic and doped materials confirmed the obtained Li2B4O7 structure and show its morphology. XRD patterns of the Li2B4O7 matched a tetragonal crystal structure. Crystals of Li2B4O7 of an average size of 50 nm were obtained. The presence of the copper dopant was confirmed in crystals of Li2B4O7:Cu by SEM-EDS (energy dispersive spectroscopy X-ray). The emission spectrum of Cu doped Li2B4O7 showed a prominent peak at 367 nm, while the main UV-Vis absorption was observed from 240 nm to 300 nm due to Cu+ ion 3d10 → 3d9 4s transitions. The thermoluminescent (TL) response was studied for both γ radiation and X-ray. A 661.7 keV γ radiation using a 137Cs source at doses of 50, 100, 200, 300, 400 and 500 mGy was applied to Li2B4O7:Cu (0.1 wt%) pellets. An X-ray source was used at doses of 600, 800 and 1000 mGy to irradiate pellets of Li2B4O7:Cu (0.02, 0.04, 0.06, 0.08 and 0.1 wt%). A linear TL response was observed for both X-ray and γ radiation. The kinetic parameters were calculated using the peak shape method for the Li2B4O7:Cu (0.1 wt%).

Wearable activity tracker study exploring rheumatoid arthritis patients' disease activity using patient-reported outcome measures, clinical measures, and biometric sensor data (the wear study).

Background: Digital health studies using electronic patient reported outcomes (ePROs), wearables, and clinical data to provide a more comprehensive picture of patient health. Methods: Newly initiated patients on upadacitinib or adalimumab for RA will be recruited from community settings in the Excellence NEtwork in RheumatoloGY (ENRGY) practice-based research network. Over the period of three to six months, three streams of data will be collected (1) linkable physician-derived data; (2) self-reported daily and weekly ePROs through the ArthritisPower registry app; and (3) biometric sensor data passively collected via wearable. These data will be analyzed to evaluate correlations among the three types of data and patient improvement on the newly initiated medication. Conclusions: Results from this study will provide valuable information regarding the relationships between physician data, wearable data, and ePROs in patients newly initiating an RA treatment, and demonstrate the feasibility of digital data capture for Remote Patient Monitoring of patients with rheumatic disease.

Metabolic-associated fatty liver voxel-based quantification on CT images using a contrast adapted automatic tool.

BACKGROUND & AIMS: Metabolic-dysfunction associated fatty liver disease (MAFLD) is highly prevalent and can lead to liver complications and comorbidities, with non-invasive tests such as vibration-controlled transient elastography (VCTE) and invasive liver biopsies being used for diagnosis The aim of the present study was to develop a new fully automatized method for quantifying the percentage of fat in the liver based on a voxel analysis on computed tomography (CT) images to solve previously unconcluded diagnostic deficiencies either in contrast (CE) or non-contrast enhanced (NCE) assessments. METHODS: Liver and spleen were segmented using nn-UNet on CE- and NCE-CT images. Radiodensity values were obtained for both organs for defining the key benchmarks for fatty liver assessment: liver mean, liver-to-spleen ratio, liver-spleen difference, and their average. VCTE was used for validation. A classification task method was developed for detection of suitable patients to fulfill maximum reproducibility across cohorts and highlight subjects with other potential radiodensity-related diseases. RESULTS: Best accuracy was attained using the average of all proposed benchmarks being the liver-to-spleen ratio highly useful for CE and the liver-to-spleen difference for NCE. The proposed whole-organ automatic segmentation displayed superior potential when compared to the typically used manual region-of-interest drawing as it allows to accurately obtain the percent of fat in liver, among other improvements. Atypical patients were successfully stratified through a function based on biochemical data. CONCLUSIONS: The developed method tackles the current drawbacks including biopsy invasiveness, and CT-related weaknesses such as lack of automaticity, dependency on contrast agent, no quantification of the percentage of fat in liver, and limited information on region-to-organ affectation. We propose this tool as an alternative for individualized MAFLD evaluation by an early detection of abnormal CT patterns based in radiodensity whilst abording detection of non-suitable patients to avoid unnecessary exposure to CT radiation. Furthermore, this work presents a surrogate aid for assessing fatty liver at a primary assessment of MAFLD using elastography data.

Fibroblast growth factor 21 is a hepatokine involved in MASLD progression.

AIM: We aimed to assess the role of FGF21 in metabolic dysfunction-associated steatotic liver disease (MASLD) at a multi-scale level. METHODS: We used human MASLD pathology samples for FGF21 gene expression analyses (qPCR and RNAseq), serum to measure circulating FGF21 levels and DNA for genotyping the FGF21 rs838133 variant in both estimation and validation cohorts. A hepatocyte-derived cell line was exposed to free fatty acids at different timepoints. Finally, C57BL/6J mice were fed a high-fat and choline-deficient diet (CDA-HFD) for 16 weeks to assess hepatic FGF21 protein expression and FGF21 levels by ELISA. RESULTS: A significant upregulation in FGF21 mRNA expression was observed in the liver analysed by both qPCR (fold change 5.32 ± 5.25 vs. 0.59 ± 0.66; p = 0.017) and RNA-Seq (3.5 fold; FDR: 0.006; p < 0.0001) in MASLD patients vs. controls. Circulating levels of FGF21 were increased in patients with steatohepatitis vs. bland steatosis (386.6 ± 328.9 vs. 297.9 ± 231.5 pg/mL; p = 0.009). Besides, sex, age, A-allele from FGF21, GG genotype from PNPLA3, ALT, type 2 diabetes mellitus and BMI were independently associated with MASH and significant fibrosis in both estimation and validation cohorts. In vitro exposure of Huh7.5 cells to high concentrations of free fatty acids (FFAs) resulted in overexpression of FGF21 (p < 0.001). Finally, Circulating FGF21 levels and hepatic FGF21 expression were found to be significantly increased (p < 0.001) in animals under CDA-HFD. CONCLUSIONS: Hepatic and circulating FGF21 expression was increased in MASH patients, in Huh7.5 cells under FFAs and in CDA-HFD animals. The A-allele from the rs838133 variant was also associated with an increased risk of steatohepatitis and significant and advanced fibrosis in MASLD patients.