Significant Steatosis Research Articles

Abstract 4141485: Liver Steatosis in Women with Coronary Microvascular Dysfunction

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) has been previously associated with coronary microvascular dysfunction (CMD) and is closely related to metabolic syndrome among men and women. Data regarding the association of quantitative liver steatosis and CMD in women with ischemia and no obstructive coronary arteries (INOCA) are scarce. Aim: To evaluate the association of liver steatosis with myocardial perfusion in women with CMD and reference controls. Methods: Women with CMD and no obstructive coronary arteries (n=55) from 2 prospective cohort studies (R01HL146158, R01HL153500) and asymptomatic age- and sex-matched reference controls (n=10) underwent stress and rest cardiac magnetic resonance imaging (MRI), with a validated MRI quantification of liver fat by proton density fat fraction (PDFF), at a single center. CMD was confirmed by coronary function testing or prior diagnostic stress tests. Parameters of liver fat and LV structure, function and myocardial perfusion reserve index (MPRI, a measure of CMD) were compared between cases and controls. A threshold of PDFF ≥5.2% was used to define significant liver steatosis. Results: Other than higher prevalence of hypertension in the CMD group, age and cardiometabolic history were not significantly different between the groups, as were the PDFF and prevalence of liver steatosis (Table). PDFF directly correlated with body mass index (r=0.41, p<0.01). There was no correlation between PDFF and MPRI (Figure). Conclusions: In this pilot study, our results suggest similar prevalence of liver steatosis between women with CMD and reference controls. Interestingly, MPRI did not correlate with PDFF, suggesting that mechanisms other than metabolic health may play a significant role in the pathophysiology of CMD among women with INOCA.

Association between liver steatosis, fibrosis, and the onset of type 2 diabetes in overweight individuals: A fibroscan-based study in Southern Italy

ObjectiveThis study aims to explore the association between liver steatosis and fibrosis, as assessed by Fibroscan, and the onset of type 2 diabetes in overweight, medication-free men and women. MethodsWe analyzed data from 164 participants with overweight or obesity (41.4 % male), including 39 individuals (23.8 %) with type 2 diabetes. All participants underwent Fibroscan to evaluate liver steatosis (CAP > 275 dBm) and fibrosis (liver stiffness > 8.2 kPa). Diabetes was diagnosed using fasting glucose, 2-hour glucose tolerance test (OGTT), and HbA1c levels. ResultsLiver steatosis was significantly more prevalent in individuals with diabetes (89.7 % vs 52 %, P < 0.001). Liver fibrosis was observed in 35.9 % of subjects with diabetes (vs 13.6 %, P = 0.002). Mean CAP (P < 0.001) and kPA (P = 0.006) values were significantly higher in the group with diabetes. Significant associations between CAP (MD: 30.87, P = 0.009) and liver stiffness (MD: 2.454, P = 0.006) with diabetes were found, independent of other variables. Additionally, liver steatosis was independently associated with elevated HOMA-IR levels (P = 0.001). ConclusionElevated liver steatosis and fibrosis are both linked to type 2 diabetes, independent of traditional risk factors. These findings support screening for diabetes in individuals with significant steatosis and fibrosis and vice versa.

Inhibiting Ferroptosis Prevents the Progression of Steatotic Liver Disease in Obese Mice

Ferroptosis, a form of regulated cell death characterized by lipid peroxidation and iron accumulation, has been implicated in the progression of metabolic-dysfunction-associated steatohepatitis (MASH) in obesity. This study investigated the role of ferroptosis in the development of hepatic steatosis and MASH in obese mice and assessed the therapeutic potential of ferrostatin-1, a ferroptosis inhibitor. C57BL/6J wild-type (n = 8) and ob/ob mice (n = 16) were maintained on a standard chow diet. Mice were divided into three groups that included C57BL/6 (n = 8), ob/ob (n = 8), and ob/ob + ferrostatin-1 (FER) (n = 8), with the latter group receiving an intraperitoneal injection of 5 μM/kg ferrostatin three times per week for eight weeks. Following treatment, serum and tissue samples were collected for analysis. Significant hepatic steatosis and increased lipogenesis markers were observed in ob/ob mice, which were restored to baseline levels in the ob/ob + FER group treated with ferrostatin-1. Elevated oxidative stress was indicated by increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels in the ob/ob group, while glutathione peroxidase 4 (GPX4) activity was significantly reduced. Ferrostatin-1 treatment decreases MDA levels and restores GPX4 activity. Additionally, ferrostatin mitigates iron overload and promotes macrophage polarization from M1 to M2, thereby reducing liver inflammation and fibrosis. Ferrostatin treatment reversed mitochondrial dysfunction in ob/ob mice. Our findings revealed that ferroptosis plays a significant role in the progression of obesity to hepatic steatosis and MASH. Inhibiting ferroptosis using ferrostatin-1 effectively improves liver histology, reduces oxidative stress, normalizes lipogenesis, and modulates macrophage polarization. This study highlights the potential of targeting ferroptosis as a therapeutic strategy for obesity-related liver diseases, warranting further investigation in clinical settings.

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

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. 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. 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. Machine learning coupled with liver texture and color analysis of photographs taken with smartphones provides excellent accuracy for determining liver steatosis.

Novel Peripherally Selective Cannabinoid Receptor 1 Neutral Antagonist Improves Metabolic Dysfunction-Associated Steatotic Liver Disease in Mice.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing globally. MASLD is characterized by clinically significant liver steatosis, and a subset of patients progress to more severe metabolic-disorder-associated steatohepatitis (MASH) with liver inflammation and fibrosis. Cannabinoid receptor 1 (CB1) antagonism is a proven therapeutic strategy for the treatment of the phenotypes that underlie MASLD, though work on early centrally penetrant compounds largely ceased following adverse psychiatric indications in humans. We present here preclinical testing of a CB1 neutral antagonist, N-[1-[8-(2-Chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4l]methanesulfonamide (RTI-348), with minimal brain exposure when administered to mice. In a diet-induced model of MASLD-induced MASH, administration of RTI-348 decreased the total body and liver weight gain. Animals treated with RTI-348 showed reduced steatosis. Furthermore, they produced lower plasma alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH), biomarkers associated with liver damage. Mice maintained on the MASH diet had elevated expression of genes associated with profibrogenesis, immune response, and extracellular matrix remodeling, and treatment with RTI-348 mitigated these diet-induced changes in gene expression. Using an intracranial electrical self-stimulation model, we also demonstrated that RTI-348 does not produce an anhedonia response, as seen with the first-generation CB1 inverse agonist rimonabant. Altogether, the results herein point to RTI-348 as a promising neutral antagonist for MASH.

FibroScan compared to liver biopsy for accurately staging recurrent hepatic steatosis and fibrosis after transplantation for MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) recurrence after liver transplantation (LT) seems unavoidable and gradual. We aimed to evaluate the diagnostic accuracy in the post-LT setting of patients transplanted for metabolic dysfunction-associated steatohepatitis (MASH) of recurrent hepatic steatosis and fibrosis identified with FibroScan, compared to biopsy findings. This prospective cohort study included adults transplanted for MASH between 2010 and 2022 in three LT centres in Spain who underwent FibroScan and biopsy at least 1-year after LT. In total, 44 patients transplanted for MASH after LT were included. The median time from LT to biopsy and FibroScan was 24.5 (interquartile range [IQR]:16-46) and 26.0 (IQR: 16.8-41.5) months, respectively. The median time between biopsy and FibroScan was 2.0 (IQR: 0-5) months. On FibroScan, significant steatosis was diagnosed in about half of the patients (n = 21, 47.7%), yet advanced fibrosis in only two cases (4.6%). On biopsy, a quarter of biopsied patients (n = 11, 25%) had a MASH diagnosis, two (4.6%) with significant fibrosis and one (2.3%) with cirrhosis. All patients with liver stiffness measurement (LSM) values <8 kPa (n = 35, 79.5%) had a fibrosis stage ≤F1 (negative predictive value = 100%). The combination of post-LT hypertension (odds ratio [OR]: 12.0, 95% confidence interval [CI]: 1.8-80.4, p = .010) and post-LT dyslipidaemia (OR: 7.9, 95% CI: 1.3-47.1, p = .024) with LSM (OR: 1.7, 95% CI: 1.1-2.8, p = .030) was independently associated with MASLD. Although biopsy remains the gold standard for detecting fibrosis, our results suggest that LSM values <8 kPa after LT for MASH are strongly correlated with absence of significant/advanced fibrosis.

Correlation between controlled attenuation parameter values with SYNTAX score in patients with significant coronary artery disease

Non-alcoholic fatty liver disease (NAFLD) is an emerging cause of chronic liver disease, with coronary artery disease (CAD) as the main cause of death in NAFLD patients. However, correlation between the severity of liver steatosis and coronary atherosclerosis is yet to be understood. Here we aim to explore the correlation between controlled attenuation parameter (CAP) values and SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) score in adult patients with significant CAD, defined as ≥ 50% stenosis of the left main coronary artery, or ≥ 70% stenosis of the other major coronary arteries. A cross-sectional study was conducted on 124 adult patients with significant CAD who underwent coronary angiography. Transient elastography with CAP was used to assess liver steatosis severity, resulting in a mean CAP value of 256.5 ± 47.3 dB/m, with 52.5% subjects had significant steatosis (CAP value of ≥ 248 dB/m). Median SYNTAX score was 22. A statistically significant correlation was observed between CAP value and SYNTAX score (r = 0.245, p < 0.0001). The correlation was more pronounced in patients with prior history of PCI (r = 0.389, p = 0.037). Patients with high-risk SYNTAX score (> 32) had the highest CAP value (285.4 ± 42.6 dB/m), and it was significantly higher than those with low-risk SYNTAX score (0–22), with a mean difference of 38.76 dB/m (p = 0.006). Patients with significant liver steatosis should undergo periodic CAD assessment and lifestyle modification, especially those with severe liver steatosis.

Regional fat distribution and hepatic fibrosis and steatosis severity in patients with nonalcoholic fatty liver disease and type 2 diabetes.

Epidemiologic findings suggest that measures of body fat distribution predict health outcomes independent of the overall body fat assessed by body mass index (BMI). This study aimed to evaluate the associations of overall and regional body fat with the severity of hepatic steatosis and fibrosis in type 2 diabetic patients with non-alcoholic fatty liver disease. Bioelectric impedance analysis and two newly developed anthropometric indices, namely, A Body Shape Index (ABSI) and Body Roundness Index (BRI), were used to estimate the body fat. Based on fibroscan parameters, significant hepatic fibrosis and severe steatosis were defined as ≥F2 and >66%, respectively. Higher total body fat (odds ratio [OR] 1.107, 95% confidence intervals (CI) 1.038-1.182, p=0.002), trunk fat (OR 1.136, 95% CI 1.034-1.248, p=0.008) and leg fat (OR 1.381, 95% CI 1.139-1.674, p=0.001) were associated with liver fibrosis. However, in contrast to the total body fat (OR 1.088, 95% CI 1.017-1.164, p=0.014) and leg fat (OR 1.317, 95% CI 1.066-1.628, p=0.011), the trunk fat was not associated with severe hepatic steatosis. BRI performed better than trunk, leg and total body fat in predicting hepatic steatosis (OR 2.186, 95% CI 1.370-3.487, p=0.001) and fibrosis (OR 2.132, 95% CI 1.419-3.204, p<0.001). Moreover, the trunk to leg fat ratio and ABSI were not independent predictors of either steatosis or fibrosis (p>0.05). BRI revealed a superior predictive ability for identifying the degree of hepatic steatosis and stiffness than other obesity indices. Additionally, higher levels of adiposity in the trunk, legs, and overall body were linked to an increased risk of developing liver fibrosis. Although trunk fat did not show an association with severe hepatic steatosis, an increase in leg and total fat was related to liver steatosis.

Oleuropein, a Component of Extra Virgin Olive Oil, Improves Liver Steatosis and Lobular Inflammation by Lipopolysaccharides-TLR4 Axis Downregulation.

Gut-dysbiosis-induced lipopolysaccharides (LPS) translocation into systemic circulation has been suggested to be implicated in nonalcoholic fatty liver disease (NAFLD) pathogenesis. This study aimed to assess if oleuropein (OLE), a component of extra virgin olive oil, lowers high-fat-diet (HFD)-induced endotoxemia and, eventually, liver steatosis. An immunohistochemistry analysis of the intestine and liver was performed in (i) control mice (CTR; n = 15), (ii) high-fat-diet fed (HFD) mice (HFD; n = 16), and (iii) HFD mice treated with 6 µg/day of OLE for 30 days (HFD + OLE, n = 13). The HFD mice developed significant liver steatosis compared to the controls, an effect that was significantly reduced in the HFD + OLE-treated mice. The amount of hepatocyte LPS localization and the number of TLR4+ macrophages were higher in the HFD mice in the than controls and were lowered in the HFD + OLE-treated mice. The number of CD42b+ platelets was increased in the liver sinusoids of the HFD mice compared to the controls and decreased in the HFD + OLE-treated mice. Compared to the controls, the HFD-treated mice showed a high percentage of intestine PAS+ goblet cells, an increased length of intestinal crypts, LPS localization and TLR4+ expression, and occludin downregulation, an effect counteracted in the HFD + OLE-treated mice. The HFD-fed animals displayed increased systemic levels of LPS and zonulin, but they were reduced in the HFD + OLE-treated animals. It can be seen that OLE administration improves liver steatosis and inflammation in association with decreased LPS translocation into the systemic circulation, hepatocyte localization of LPS and TLR4 downregulation in HFD-induced mouse model of NAFLD.

Assessing hepatic steatosis by magnetic resonance in potential living liver donors

To determine the accuracy of magnetic resonance imaging-proton density fat fraction (MRI-PDFF) measurements for detecting liver fat content in potential living liver donors and to compare these results using liver biopsy findings. A total of 139 living liver donors (men/women: 83/56) who underwent MRI between January 2017 and September 2021 were included in this analysis retrospectively. The PDFFs were measured using both MR spectroscopy (MRS) and chemical shift-based MRI (CS-MRI) for each donor in a blinded manner. Significant positive correlations were found between liver biopsy and MRS-PDFF and CS-MRI PDFF in terms of hepatic steatosis detection [r = 0.701, 95% confidence interval (CI): 0.604–0.798, r = 0.654, 95% CI: 0.544–0.765, P < 0.001, respectively). A weak level correlation was observed between liver biopsy, MRI methods, and vibration-controlled transient elastography attenuation parameters in 42 available donors. Based on receiver operating characteristic (ROC) analysis, MRS-PDFF and CS-MRI PDFF significantly distinguished >5% of histopathologically detected hepatic steatosis with an area under the ROC curve (AUC) of 0.837 ± 0.036 (P < 0.001, 95% CI: 0.766–0.907) and 0.810 ± 0.036 (P < 0.001, 95% CI: 0.739–0.881), respectively. The negative predictive values (NPVs) of MRS-PDFF and CS-MRI PDFF were 88.3% and 81.3%, respectively. In terms of distinguishing between clinically significant hepatic steatosis (≥10% on histopathology), the AUC of MRS-PDFF and CS-MRI were 0.871 ± 0.034 (P < 0.001 95% CI: 0.804–0.937) and 0.855 ± 0.036 (P < 0.001, 95% CI: 0.784–0.925), respectively. The NPVs of MRS-PDFF and CS-MRI were 99% and 92%, respectively. The methods of MRS-PDFF and CS-MRI PDFF provide a non-invasive and accurate approach for assessing hepatic steatosis in potential living liver donor candidates. These MRI PDFF techniques present a promising clinical advantage in the preoperative evaluation of living liver donors by eliminating the requirement for invasive procedures like liver biopsy.

Combined exposure of polystyrene microplastics and benzo[a]pyrene in rat: Study of the oxidative stress effects in the liver

Microplastics (MPs) and benzo[a]pyrene (B[a]P) are prevalent environmental pollutants. Numerous studies have extensively reported their individual adverse effects on organisms. However, the combined effects and mechanisms of exposure in mammals remain unknown. Thus, this study aims to investigate the potential effects of oral administration of 0.5μm polystyrene (PS) MPs (1 mg/mL or 5 mg/mL), B[a]P (1 mg/mL or 5 mg/mL) and combined (1 mg/mL or 5 mg/mL) on 64 male SD rats by gavage method over 6-weeks. The results demonstrate that the liver histopathological examination showed that the liver lobules in the combined (5 mg/kg) group had blurred and loose boundaries, liver cord morphological disorders, and significant steatosis. The levels of AST, ALT, TC, and TG in the combined dose groups were significantly higher than those in the other groups, the combined (5 mg/kg) group had the lowest levels of antioxidant enzymes and the highest levels of oxidants. The expression of Nrf2 was lowest and the expression of P38, NF-κB, and TNF-α was highest in the combined (5 mg/kg) group. In conclusion, these findings indicate that the combination of PSMPs and B[a]P can cause the highest levels of oxidative stress and elicit markedly enhanced toxic effects, which cause severe liver damage.

A Simple and Reliable 2D-Shear Wave Elastography and UltraSound Coefficient Attenuation Parameter Technique in Chronic Liver Diseases.

The performance and reliability criteria for Aixplorer MACH30 (SS) in chronic liver diseases (CLD) have not been validated. The objectives were to define the optimal procedure, the accuracy for fibrosis and steatosis diagnosis, and the reliability criteria using SS. Patients had 2D-shear wave elastography (SWE) and ultraSound-guided controlled attenuation parameter (SCAP) performed in triplicate at the mid-axillary line (MAL), posterior axillary line (PAL), and anterior axillary line (AAL). Performances of SWE and SCAP were defined using transient elastography (TE ≥ 9.5kPa) and CAP (≥ 275dB/m) using Fibroscan (FS) as reference and validated with liver biopsy (LB). FS and SS data from 203 CLD patients were analyzed (55 ± 14years; 59% male; MASLD 58%). Median TE and CAP were 6.4kPa (2.5-66.9) and 270dB/m (141-400). The best technique for the diagnosis of advanced fibrosis and significant steatosis was the median of three SWE values and three SCAP values at MAL, PAL, and AAL with an AUROC of 0.96 [95% CI 0.93-0.98] and 0.91 [95% CI 0.86-0.95]. Only skin-to-liver distance ≥ 2.4cm (p = 0.012, 95% CI 1.37-13.38) was independently associated with discordance. The accuracy of SWE (≥ 8.5kPa) and SCAP (≥ 0.44) was analyzed in 58 patients with LB. The PPV and NPV were 50% and 94%, and 71% and 88% for fibrosis and steatosis, respectively. A reliable diagnosis of advanced fibrosis and significant steatosis can be obtained with the median of three measurements in different liver portions using SS. The only non-reliable criterion is skin-to-liver distance ≥ 2.4cm.

Hepatic steatosis: Qualitative and quantitative sonographic assessment in comparison to histology.

Globally, B-mode ultrasound is the most common modality used for the diagnosis of hepatic steatosis. We aimed to assess the correlation between qualitative liver ultrasound parameters, attenuation imaging (ATI) and histopathology-diagnosed steatosis grade obtained from liver biopsy. Our secondary aim was to examine the interobserver variability of qualitative ultrasound features. A retrospective cohort study was performed which included adult patients (age ≥ 18 years) who had same-day liver ultrasound, ATI and liver biopsy for grading hepatic steatosis severity between 2018 and 2022. The qualitative US features for hepatic steatosis were independently scored by three radiologists and interobserver variability was examined. Histologic steatosis grade, ATI and qualitative ultrasound parameters were compared. Ninety patients were included; 67% female with a median age of 54 (IQR 39-65) years. The radiologist's overall impression had the highest correlation (very strongly correlated) with histologic steatosis grade (r = 0.82, P < 0.001). ATI coefficient and all qualitative ultrasound B-mode features except for liver echotexture and focal fat sparing were strongly correlated with histologic steatosis grade (r ≥ 0.70, P < 0.001). Most qualitative ultrasound features had good agreement between observers (Kappa statistic 0.61-1.0, P < 0.001), (Kendall coefficient 0.92, P < 0.001). The examined qualitative ultrasound parameters and ATI had good-excellent performance for diagnosing clinically significant hepatic steatosis; however, the radiologist's overall impression had the best correlation with histologic steatosis grade. Our findings suggest an ongoing role for qualitative liver ultrasound assessment of hepatic steatosis despite the emergence of newer quantitative measures.

Metabolic syndrome is associated with significant hepatic fibrosis and steatosis in patients with nonalcoholic steatohepatitis

Background and aimsNonalcoholic steatohepatitis (NASH), an inflammatory form of non-alcoholic fatty liver disease, can progress to advanced liver fibrosis, cirrhosis, and liver cancer. Metabolic syndrome (MetS) parallels the prevalence of non-alcoholic fatty liver disease/NASH and increases patients’ risk of advanced liver disease. This study aimed to determine whether MetS was associated with the histological progression of NASH. MethodsPatients with liver biopsy-proven NASH were retrospectively screened and categorized into two groups for each histological feature: with (<2 points) or without (≥2 points) significant hepatic steatosis/inflammation/fibrosis. Multivariable logistic regression was used to explore the association between MetS and histological features. ResultsIn total, 386 patients with a median age of 33.0 years were enrolled; among them, 35.2% were female, and 41.2% had MetS. The proportion of significant hepatic fibrosis and steatosis in those with MetS was significantly higher than in those without MetS (p < 0.05). Multivariable logistic regression analyses showed that MetS remained significantly associated with significant hepatic fibrosis (adjusted odds ratio: 1.852, 95% confidence interval: 1.042–3.292, p = 0.036), and severe hepatic steatosis (adjusted odds ratio: 2.008, 95% confidence interval: 1.030–3.914, p = 0.041). ConclusionMetS was associated with significant hepatic fibrosis and steatosis in patients with NASH. Our results suggest that NASH patients with MetS should be closely monitored and given targeted intervention and treatment, which may help to prevent disease progression and mitigate the growing burden of NASH.

MRI Dixon Fat-Corrected Look-Locker T1 Mapping for Quantification of Liver Fibrosis and Inflammation-A Comparison With the Non-Fat-Corrected Shortened Modified Look-Locker Inversion Recovery Technique.

This study evaluates the impact of liver steatosis on the discriminative ability for liver fibrosis and inflammation using a novel Dixon water-only fat-corrected Look-Locker T1 mapping sequence, compared with a standard shortened Modified Look-Locker Inversion Recovery (shMOLLI) sequence, with the aim of overcoming the limitation of steatosis-related confounding in liver T1 mapping. 3 T magnetic resonance imaging of the liver including the 2 T1 mapping sequences and proton density fat fraction (PDFF) was prospectively performed in 24 healthy volunteers and 38 patients with histologically proven liver fibrosis evaluated within 90 days of liver biopsy. Paired Mann-Whitney test compared sequences between participants with and without significant liver steatosis (PDFF cutoff 10%), and unpaired Kruskal-Wallis test compared healthy volunteers to patients with early (F0-2) and advanced (F3-4) liver fibrosis, as well as low (A0-1) and marked (A2-3) inflammatory activity. Univariate and multivariate logistic regression models assessed the impact of liver steatosis on both sequences. Dixon_W T1 was higher than shMOLLI T1 in participants without steatosis (median 896 ms vs 890 ms, P = 0.04), but lower in participants with liver steatosis (median 891 ms vs 973 ms, P < 0.001). Both methods accurately differentiated between volunteers and patients with early and advanced fibrosis (Dixon_W 849 ms, 910 ms, 947 ms, P = 0.011; shMOLLI 836 ms, 918 ms, 978 ms, P < 0.001), and those with mild and marked inflammation (Dixon_W 849 ms, 896 ms, 941 ms, P < 0.01; shMOLLI 836 ms, 885 ms, 978 ms, P < 0.001). Univariate logistic regression showed slightly lower performance of the Dixon_W sequence in differentiating fibrosis (0.69 vs 0.73, P < 0.01), compensated by adding liver PDFF in the multivariate model (0.77 vs 0.75, P < 0.01). Dixon water-only fat-corrected Look-Locker T1 mapping accurately identifies liver fibrosis and inflammation, with less dependency on liver steatosis than the widely adopted shMOLLI T1 mapping technique, which may improve its predictive value for these conditions.

Do Hepatic Fibrosis and Steatosis Measured by Hepatic Transient Elastography (FibroScan) Predict Cardiovascular Risk in Patients with Non-alcoholic Fatty Liver Disease: An Observational Cross-sectional Study

Objectives: Non-alcoholic fatty liver disease (NAFLD) has been associated with increased cardiovascular risk (CVR) in the previous studies. In the majority, ultrasonography has been used to diagnose and stage NAFLD, which lacks sensitivity and is non-quantitative. Other more sensitive, comprehensive, and quantitative diagnostic tools such as vibration-controlled transient elastography (TE) have largely been underused in research work. TE-driven liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) provide an accurate and simplified estimation of liver fibrosis and steatosis, respectively. Therefore, we aimed to analyze the association between these two objective, robust parameters and CVR. Materials and Methods: In this observational cross-sectional study, NAFLD participants were divided into two distinct categories of steatosis (CAP &lt;290 and ≥290 dB) and fibrosis (LSM &lt;10 and ≥10 kPa). Their CVR assessment was done by calculating Framingham risk score (FRS), American College of Cardiology/American Heart Association Pooled Cohort Equation Score (ACC/AHA PCES), and carotid intimal medial thickness (CIMT). Results: A greater number of participants presented with mild-moderate fibrosis (n = 41, 62.1%) as compared to severe fibrosis (n = 25, 37.8%) whereas severe steatosis participants predominated (n = 52, 78%) as compared to mild-moderate steatosis. The presence of significant fibrosis (LSM ≥10 kPa) was independently and significantly associated with FRS, ACC/AHA PCES, and CIMT. On the other hand, the presence of significant steatosis (CAP ≥290 dB/m) was not significantly associated with any CVR marker (FRS, ACC/AHA PCES, or CIMT), though a greater number of participants with CIMT &gt;0.7 belonged to severe steatosis group. Conclusion: Subjects with severe fibrosis (LSM ≥10) had a significantly higher CVR, whereas severe steatosis (CAP ≥290) alone failed to predict CVR. Therefore, CVR reduction strategies can be targeted primarily in NAFLD subjects with fibrosis, particularly in resource-limited healthcare settings.

Nanoparticles alleviate non-alcoholic steatohepatitis via ER stress sensor-mediated intestinal barrier damage and gut dysbiosis.

The gut microbiota plays an important role in the development of non-alcoholic steatohepatitis (NASH), but the underlying mechanism is unclear. It has been found that the transcription factor XBP1s plays an important role in regulating inflammation and lipid metabolism and maintaining the integrity of intestinal barrier. However, whether XBP1s modulates the development of NASH by regulating the integrity of the intestinal barrier and altering the composition of the gut microbiota remains unknown. Mice fed with a fat-, fructose-, cholesterol-rich (FFC) diet for 24 weeks successfully established the NASH model, as demonstrated by significant hepatic steatosis, inflammation, hepatocyte injury and fibrosis. The profile of gut microbiota dynamically changed with the different stages of NAFLD via 16S rDNA sequencing the feces from mice fed with FFC diet for 0, 12, or 24 weeks or NASH mice treated with siRNA-loaded folic acid-modified TPGS (hereafter named FT@XBP1). NASH mice had significantly higher abundance of Firmicutes, Blautia and Bacteroides, and lower abundance of Bifidobacterium and GCA-900066575. FT@XBP1 supplementation had a significantly attenuated effect on FFC diet-induced weight gain, hepatic fat accumulation, dyslipidemia, inflammatory cytokines, ER stress and fibrosis. In particularly, FT@XBP1 modulates the composition of the intestinal flora; for example, NASH mice demonstrated higher abundance of Blautia and Bacteroides, and lower abundance of Actinobacteriota, Muribaculaceae and Bifidobacterium, which were partially restored by FT@XBP1 treatment. Mechanistically, FT@XBP1 increased the expression of ZO-1 in the intestine and had the potential to restore intestinal barrier integrity and improve antimicrobial defense to alleviate enterogenic endotoxemia and activation of inflammatory signaling pathways. Regulation of the key transcription factor XBP1s can partially restore the intestinal microbiota structure, maintain the integrity of intestinal mucosal barrier, and prevent the progression of NASH, providing new evidence for treating NASH.

Compromised very-low density lipoprotein induced polyunsaturated triglyceride accumulation in N-nitrosodiethylamine-induced hepatic steatosis

N-Nitrosodiethylamine (NDEA), a carcinogen in some foods and medications, is linked to liver damage similar to non-alcoholic fatty liver disease (NAFLD). This study explores how NDEA disrupts liver lipid metabolism. Sprague-Dawley rats were given two doses of NDEA (100 mg/kg) orally, 24 h apart. Liver response was assessed through tissue staining, blood tests, and biochemical markers, including fatty acids, lipid peroxidation, and serum very-low density lipoprotein (VLDL) levels. Additionally, lipidomic analysis of liver tissues and serum was performed. The results indicated significant hepatic steatosis (fat accumulation in the liver) following NDEA exposure. Blood analysis showed signs of inflammation and liver damage. Biochemical tests revealed decreased liver protein synthesis and specific enzyme alterations, suggesting liver cell injury but maintaining mitochondrial function. Increased fatty acid levels without a rise in lipid peroxidation were observed, indicating fat accumulation. Lipidomic analysis showed increased polyunsaturated triglycerides in the liver and decreased serum VLDL, implicating impaired VLDL transport in liver dysfunction. In conclusion, NDEA exposure disrupts liver lipid metabolism, primarily through the accumulation of polyunsaturated triglycerides and impaired fat transport. These findings provide insight into the mechanisms of NDEA-induced liver injury and its progression to hepatic steatosis.

THE IMPACT OF VITAMIN D ON HEPATIC ENZYMES AND NON-ALCOHOLIC FATTY LIVER DISEASE ACROSS–SECTIONAL STUDY

Non-Alcoholic Fatty Liver Disease (NAFLD) has become increasingly common globally, raising serious concerns for public health. NAFLD is a complex and multifaceted disease that includes a range of liver diseases, such as cirrhosis, non-alcoholic steatohepatitis (NASH), and simple hepatic steatosis. A combination of environmental, metabolic, and genetic factors causes it. Recent data suggests that vitamin D, a fat-soluble vitamin with various physiological roles, may be crucial for liver health and the development of NAFLD. This cross-sectional study aimed to investigate vitamin D's potential impact on liver function and the development of NAFLD. A Cross-Sectional Study was conducted at the Department of Medicine, MTI, LRH, Peshawar, from August 2019 to January 2020. Participants for this study were selected from the Department of Medicine at MTI, LRH, Peshawar, between August 2019 and January 2020. The study population included individuals with NAFLD identified by laboratory, radiographic, and clinical criteria. Blood samples were taken to measure the serum levels of vitamin D and liver enzymes, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Additional clinical and demographic information was also collected. The average age of the participants in this study was forty years, and there was an equal distribution of genders. Following treatment, the severity of NAFLD significantly decreased. At the beginning of the study, 12.3% of participants had severe steatosis, 40.3% had moderate, and 48.4% had mild steatosis. After treatment, 40.3% of patients had no steatosis, 47.8% had mild steatosis, and 17% had significant steatosis. ALT, ALP, and bilirubin levels showed significant improvements in liver function, with p-values &lt;0.05. While an increase in ALP indicated improved liver function, decreased ALT levels demonstrated reduced liver inflammation. Lower bilirubin levels indicated improved liver health. These findings suggest that treatment, possibly involving vitamin D supplementation, improved liver function and reduced the severity of NAFLD, highlighting the need for further research. This study indicates that vitamin D supplementation may benefit liver function and non-alcoholic fatty liver disease severity. The findings suggest that vitamin D may be a helpful treatment option for managing NAFLD, calling for further investigation and clinical testing.

OR24-05 High Waist Circumference Is Strongly Predictive Of Hepatic Steatosis And Significant Fibrosis

Abstract Disclosure: N. Janakiram: None. S. Puri: None. A. Thirumalai: None. Vibration-controlled transient elastography (TE) can measure controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) in non-alcoholic fatty liver disease (NAFLD) patients. A high skin-to-capsule distance can challenge the accuracy of this imaging technique. Therefore, high waist circumference (WC), a known risk factor for NAFLD, can hamper assessment in high-risk patients. Studies investigating the relationship between WC and TE measurements have yielded conflicting results. We used the 2017-2018 National Health and Nutrition Examination Survey (NHANES) data to explore this relationship in a large cohort of the general population. We hypothesized that high WC would be associated with (1) higher failure rate for completion of TE, (2) worse CAP and LSM measurements and (3) be predictive of presence of steatosis and significant fibrosis. We summarized the primary reason for incomplete TE in normal and high WC participants of male (M; WC ≥ 102 cm = high) and female (F; WC ≥ 88 cm = high) gender. We compared mean CAP and LSM between normal and high WC participants using unpaired t-tests. We calculated area under receiver operator curve (AUROC) for WC predicting presence of steatosis (CAP ≥248 dB/m) and significant fibrosis (LSM ≥8 kPa) and compared this with fibrosis-4 (FIB-4) and NAFLD fibrosis scores (NFS). We analyzed the 5757 patients (2880 F, 2877 M) with complete or partial TE status, based on WC. Proportion of patients with partial TE status was higher in those with high WC (8.9% F, 9% M) than normal WC patients (6.5% F, 6.4% M). We analyzed the 446 patients with partial TE status (231 F, 215 M) by cause. The proportion of patients who were unable to complete TE, either due to an IQR/medium &amp;gt; 30% or not having 10 valid measurements among the high WC population (66%) was significantly higher than those with normal WC (23%), in both women (X2 (1, n=231) = 29.63; p&amp;lt;.001) and men (X2 (1, n=215) = 49.43; p&amp;lt;.001).Among those with complete TE (n=2313; 1090 M, 1223 F), mean CAP was significantly higher (p&amp;lt;0.001) in high WC patients (308 dB/m M, 278 dB/m F) compared to normal WC patients (250 dB/m M, 225 dB/m F). Mean LSM was significantly higher (p&amp;lt;0.001) in high WC patients (6.8 kPa M, 5.7 kPa F) compared to normal WC patients (5.7 kPa M, 4.5 kPa F). The AUROC for WC predicting presence of steatosis was 0.77 in F and 0.80 in M (p&amp;lt;0.001 for both). The AUROC for WC predicting the presence of significant fibrosis (≥8 kPa) was 0.73 in F and 0.71 in M (p&amp;lt;0.001 for both). In AUROC analyses, WC performed better than FIB-4 and NFS in predicting presence of significant fibrosis and steatosis. Therefore, we conclude that high WC is more likely to result in an incomplete TE, but among those with a valid exam, it is highly predictive of presence of steatosis and significant fibrosis. Presentation: Saturday, June 17, 2023