Nonalcoholic Fatty Liver Disease Fibrosis Research Articles

Differential effects of systemic immune inflammation indices on hepatic steatosis and hepatic fibrosis: evidence from NHANES 1999–2018

BackgroundSeveral studies have demonstrated that systemic immune inflammation index (SII) has a positive relationship with hepatic steatosis. However, it is lack of system evidence for the correlation between SII and hepatic fibrosis. The objective of this study was to evaluate the relationships between SII and hepatic steatosis or hepatic fibrosis.MethodsA cross-sectional analysis was performed from the National Health and Nutrition Examination Survey (NHANES). Fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS) and hepamet fibrosis score (HFS) were the indicators for hepatic fibrosis; fatty liver index (FLI), NAFLD liver fat score (LFS) and Framingham steatosis index (FSI) were the indicators for hepatic steatosis. Pearson’s test, generalized linear model (GLM) and restricted cubic splines (RCS) were used to analyze associations of SII with hepatic fibrosis and hepatic steatosis.ResultsA total of 21,833 participants were enrolled in the study. Pearson’s test and GLM revealed that there were negative relationships between SII and hepatic fibrosis (FIB-4, NFS and HFS), while positive relationships between SII and hepatic steatosis (FLI, LFS and FSI). The corresponding β (95%CI) of SII and hepatic fibrosis were − 0.35(-0.46, -0.24), -0.67(-0.71, -0.63) and − 0.10(-0.12, -0.09), respectively. The corresponding β (95%CI) of SII and hepatic steatosis were 6.12(4.75, 7.50), 0.22(0.12, 0.31) and 0.27(0.20, 0.34), respectively. Statistically significant non-linear association were found in SII with hepatic fibrosis and hepatic steatosis in RCS model (all P < 0.001).ConclusionThere was a negative significant association between SII and hepatic fibrosis, while a positive significant association between SII and hepatic steatosis.

Standardized evaluation of diabetic retinopathy using artificial intelligence and its association with metabolic dysfunction-associated steatotic liver disease in Japan: A cross-sectional study.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in patients with obesity and diabetes and can lead to serious complications. This study aimed to evaluate fundus photographs using artificial intelligence to explore the relationships between diabetic retinopathy (DR), MASLD, and related factors. In this cross-sectional study, we included 1,736 patients with a history of diabetes treatment or glycated hemoglobin (HbA1c) levels of ≥6.5%. All participants were negative for hepatitis B surface antigen and hepatitis C virus antibody and were selected from 33,022 examinees at a health facility in Japan. Fundus photographs were analyzed using RetCAD software, and DR scores were quantified. The presence of DR was determined using two cutoffs: sensitivity (CO20) and specificity (CO50). Steatotic liver (SL) stages were assessed via ultrasound and fibrosis indices and classified into three groups: no SL (SL0), SL with low fibrosis (SL1), and SL with high fibrosis (SL2). Odds ratios (ORs) for the risk of DR associated with each SL stage were calculated using logistic regression, adjusted for age, sex, body mass index, HbA1c, C-reactive protein level, and alcohol consumption. The risk of DR was lower in the SL1 (OR: 0.63, 0.54) and SL2 (OR: 0.64, 0.77) groups compared to the SL0 group at CO20 for both the Fibrosis-4 Index (FIB-4) and the non-alcoholic fatty liver disease fibrosis score (NFS), respectively. Additionally, higher levels of cholinesterase were consistently associated with a reduced risk of DR (FIB-4: OR 0.52, NFS: OR 0.54) at CO50. This study demonstrates that MASLD was associated with a reduced risk of DR, with cholinesterase levels providing further protective effects, highlighting the need for further research into the protective mechanisms and refinement of DR evaluation techniques. The standardized AI evaluation method for DR offers a reliable approach for analyzing retinal changes.

Examining the prevalence of hepatic steatosis and advanced fibrosis using non-invasive measures across Canada: A national estimate using the Canadian Health Measures Survey (CHMS) from 2009-2019

Prevalence estimates are crucial for enhancing preparedness to prevent and manage chronic diseases. This is the first study to estimate the prevalence of hepatic steatosis and advanced fibrosis in Canada, leveraging a nationally representative survey and multiple validated non-invasive tests (NITs). The Canadian Health Measures Survey (CHMS) is Canada's largest direct health measures survey, which collects data on sociodemographic, clinical factors, and blood chemistry. We determined steatosis using two NITs: the Hepatic Steatosis Index (HSI) and the NAFLD Ridge Score (NRS). The FIB-4 Index and NAFLD fibrosis score (NFS) were used to assess the risk of advanced fibrosis among adults with steatosis. Survey weights were incorporated to account for oversampling, survey nonresponse, and post-stratification. Between 2009 and 2019, 1365 children (55% males, median age 13 (IQR: 10-15) and 4664 adults (51% males, median age 45 (IQR: 34-62), 57% reporting weekly alcohol consumption) were included in our study. The weighted steatosis prevalence ranged from 9-11% among children to 38-48% among adults based on the NRS and HSI, respectively. Between 86-87% of adults with type 2 diabetes and 65-72% with hypertension had evidence of steatosis. Overall, 1.2-2.4% of adults with steatosis were at risk of advanced liver fibrosis. We estimate between 1 in 3 and 1 in 2 adults have hepatic steatosis, and 195,000-406,200 are at high risk of advanced liver fibrosis in Canada. No routine screening guidelines for liver fibrosis exist in Canada, and most patients are unaware of their condition. Prevalence studies are essential for raising awareness and advocating for the inclusion of steatotic liver disease on national public health agendas.

Aspartate aminotransferase-to-platelet ratio index outperforms Fibrosis-4 in 2843 Korean patients with metabolic dysfunction-associated steatotic liver disease.

The definition of metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been proposed. We aim to investigate the diagnostic efficacy of noninvasive fibrosis markers in predicting liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), and MASLD. This retrospective study involved 2843 patients diagnosed with steatotic liver disease at six tertiary hospitals in South Korea. Liver fibrosis was assessed using vibration-controlled transient elastography, and various noninvasive markers, including the aspartate aminotransferase-to-platelet ratio index (APRI), Fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), and serum Mac-2-binding protein glycosylation isomer were analyzed. Among 1106 patients, 79.9% met criteria for NAFLD, MAFLD, and MASLD. The APRI had area under the receiver operating characteristic curve (AUC) values of 0.819, 0.821, and 0.818 for liver fibrosis≥F2, and 0.819, 0.824, and 0.884 for liver fibrosis≥F3, and 0.890, 0.884, and 0.889 for fibrosis≥F4 in NAFLD, MAFLD, and MASLD, respectively. The FIB-4 index showed AUC values of 0.776, 0.793, and 0.778 for fibrosis≥F2, 0.788, 0.814, and 0.79 for fibrosis≥F3, and 0.846, 0.859, and 0.856 for fibrosis≥F4. The APRI consistently had the highest AUC values, except in individuals older than 64years for fibrosis≥F4. The APRI was the most effective noninvasive fibrosis marker across NAFLD, MAFLD, and MASLD, particularly in age-stratified analyses. Further research is needed to establish standardized cut-off values and enhance the clinical utility of these markers in managing liver fibrosis.

A Clinical Algorithm for Screening Compensated Advanced Chronic Liver Disease Utilizing Ultrasonography, Platelet Count, and Albumin Levels, With Transient Elastography as Reference.

Background and aims Compensated advanced chronic liver disease (cACLD) refers to asymptomatic patients with advanced fibrosis who do not yet exhibit clinical or radiological signs of portal hypertension. Early detection of cACLD is essential for effective risk stratification and timely management, potentially preventing progression to more severe and irreversible stages of liver disease. Transient elastography (TE) is the primary diagnostic method for cACLD, with several diagnostic thresholds commonly used. Ultrasonography (USG) is widely used as an initial diagnostic tool for liver disease, but its effectiveness in diagnosing cACLD is not well established. To the best of our knowledge, this study is the first to systematically evaluate the diagnostic accuracy of USG in detecting cACLD, using TE as a reference standard based on validated diagnostic thresholds. We also examined whether combining USG findings with platelet count and serum albumin could enhance diagnostic utility. Additionally, we discuss the strengths and limitations of established non-invasive scoring systems, including the Enhanced Liver Fibrosis (ELF) test, Fibrosis-4 (Fib-4) index, and Nonalcoholic Fatty Liver Disease Fibrosis Score (NFS), to determine if our approach offers a more accessible and practical solution in clinical settings Methods This retrospective cross-sectional study was conducted at the Royal Wolverhampton NHS Trust,Wolverhampton, England, including patients with suspected liver disease who underwent USG, TE, and blood tests. Valid TE readings followed manufacturer guidelines, and patients with USG-detected portal hypertension or confounding conditions (e.g., acute hepatitis, heart failure) were excluded. We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of USG against TE, with TE values >15 kPa confirming and <10 kPa excluding cACLD. Results Among 1,528 patients (mean age 51 years, range 16-89), 982 were male (64.3%) and 546 were female (35.7%). The cohort predominantly comprised Caucasian (n=1,087, 71.1%) and South-East Asian (n=256, 16.8%) patients. USG showed a sensitivity of 64.6% (95%CI: 58.3-70.6%) and specificity of 78.2% (95%CI: 75.6-80.6%) for cACLD, with a PPV of 40.2% (95%CI: 36.7-43.7%) and an NPV of 90.7% (95%CI: 89.2-92.1%). High NPV was consistent across all etiologies. In patients with a normal liver on USG, NPV improved to 92.7% (95%CI: 90.9-94.6%) when serum albumin >35 g/L and platelet count >150 x 109/L were present. In patients with sonographic signs of liver disease, PPV increased to 84.1% (95%CI: 73.3-94.9%) when platelet count and albumin were low but dropped to 20.8% (95%CI: 15.4-26.3%) when both were normal. Conclusions USG alone has limited reliability in diagnosing cACLD but is valuable for ruling out advanced fibrosis in asymptomatic patients due to its high NPV. Adding platelet and albumin levels improves diagnostic accuracy, though TE remains essential for definitive diagnosis. This approach may streamline screening and optimize resource use, particularly in settings with limited TE access. USG combined with platelet count and serum albuminoffers a cost-effective, accessible, and practical solution for the initial assessment of cACLD. Further studies are needed to validate these findings in broader populations.

Non-invasive testing in metabolic dysfunction-associated steatotic liver disease.

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

Abstract 4140119: Liver Steatosis and Liver Fibrosis Predict Major Adverse Cardiovascular Events in the CLEAR Outcomes Trial

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), and progressive stages accompanied by liver fibrosis (LF), have been associated with liver-related and CV complications in middle-aged patients, although data on the latter is limited. Objectives: We evaluated whether liver steatosis (LS) or LF are associated with CV outcomes in a large clinical trial that included patients at high CV risk who were statin intolerant (SI), and if so, whether bempedoic acid (BA) treatment reduces observed increases in CV risk. Methods: CLEAR Outcomes evaluated the efficacy of BA in 13,970 SI patients randomized to BA (180 mg daily) or placebo and followed for a median of 40.6 months. The primary outcome was a 4-component major adverse CV event (MACE4: nonfatal MI, nonfatal stroke, coronary revascularization, or CV death). This post-hoc analysis used the following non-invasive algorithms to estimate the presence of LS and LF at baseline: Framingham Steatosis Index (FSI), Fibrosis-4 Index (FIB-4) and NAFLD Fibrosis Score (NFS). Continuous variables were reported as mean±SD, categorical variables as proportion. Time-to-event data were analysed using a Cox proportional hazards model. Adjusted hazard ratios (aHR) for every 1 unit increase in score, while holding every other variable constant, and corresponding 95% CI were reported. Results: The mean age of included participants was 66±9 years, 48% were female, mean BMI was 30±5 kg/m 2 , and characteristics were balanced over the treatment arms. Baseline FSI was 0.2±1.5, FIB-4 1.3±0.6 and NFS -0.6±1.2. LS was associated with an increased incidence of MACE4 in the whole study population, as indicated by the aHR of 1.09 (1.06-1.12) for 1 unit of FSI increase. LF was also associated with increased risk of MACE4 in the overall population, aHR 1.19 (1.11-1.28) for 1 unit of FIB-4 increase, and aHR 1.14 (1.10-1.19) for 1 unit of NFS increase. For LS, per 1 unit of FSI increase the aHR for MACE4 was lower in the treatment group: aHR of 1.04 (0.99-1.09) for BA vs 1.14 (1.09-1.18) for placebo, interaction p=0.004. For LF, aHR did not differ between groups and no significant interaction with treatment was observed. Conclusion: Both LS and LF are associated with an increased risk of MACE4. Overall, BA was associated with lower rates of MACE4 across categories of LS and LF (data not shown). A lower risk of LS-associated MACE4 was observed in the BA group. These benefits are less clear regarding the MACE4 risk driven by LF.

Sequential Diagnostic Approach Using FIB-4 and ELF for Predicting Advanced Fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease.

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

Association Between Noninvasive Liver Fibrosis Scores and Heart Failure in a General Population.

The association between nonalcoholic fatty liver disease and cardiovascular disease is firmly established, yet the association between noninvasive liver fibrosis scores and cardiovascular events remains a topic of uncertainty. Our study aimed to explore the association between liver fibrosis and heart failure. The data set was from the National Health and Nutrition Examination Survey 2011 to 2018. Advanced hepatic fibrosis risk was assessed through 3 noninvasive liver fibrosis scores: Fibrosis-4 score (FIB-4), the nonalcoholic fatty liver disease fibrosis score (NFS), and the aspartate aminotransferase to platelet ratio index (APRI). We included 19 695 eligible participants. The national prevalence of advanced liver fibrosis risk in the United States was 4.20%, 8.06%, and 0.35% as determined by FIB-4, NFS, and APRI scores, respectively. Weighted logistic regression analysis revealed significant associations between advanced liver fibrosis risk and the prevalence of heart failure (continuous variables, FIB-4: odds ratio [OR], 1.15 [95% CI, 1.07-1.23]; NFS: OR, 1.42 [95% CI, 1.23-1.64]; APRI: OR, 1.44 [95% CI, 1.15-1.81]). When the scores were assessed as categorical variables, the results were still significant (FIB-4 ≥2.67 versus FIB-4 <1.3: OR, 2.18 [95% CI, 1.47-3.24]; NFS ≥0.675 versus NFS <-1.455: OR, 2.53 [95% CI, 1.37-4.68]). Subgroup analysis found that the association between APRI and heart failure was stronger in female patients. In the general US population, the prevalence of advanced liver fibrosis risk varied between 0.35% and 8.06% as indicated by noninvasive liver fibrosis scores. FIB-4, NFS, and APRI scores were linked to an elevated prevalence of heart failure.

Burden of liver steatosis and liver fibrosis in a large cohort of people living with HIV.

Liver steatosis (LS) and liver fibrosis (LF) can increase the risk of cardiovascular disease in people with HIV, but their prevalence and associated factors are poorly understood. This study aimed to assess the prevalence of and factors associated with LS and LF in a large cohort of people with HIV. We conducted a cross-sectional study of consecutive people with HIV attending the Clinic of Barcelona from September 2022 to September 2023, excluding those with chronic B or/and C hepatitis virus coinfection. LS was assessed using the Hepatic Steatosis Index (HSI) and Fatty Liver Index (FLI), and LF was assessed using the Non-Alcoholic Fatty Liver Disease Fibrosis Score (NFS), Fibrosis-4 score (FIB-4), and the European AIDS Clinical Society (EACS) algorithm in both the whole cohort (cohort 1) and in a specific cohort more susceptible to liver disease (cohort 2). We identified independent variables associated with LS and LF using logistic regression. Cohort 1 included 4664 people with HIV; 76% and 37% of them had available HSI and FLI data, LS was present in 28% and 19%, respectively. LF risk was present in 1%, 2%, and 1% of people with HIV according to NFS, FIB-4, and EACS algorithm scores, respectively. Cohort 2 included 1345 people with HIV; 60% and 30% of them had available HSI and FLI data, LS affected 55% and 43% and LF 2%, 5%, or 3%, respectively. Factors associated with LS included current CD4 cell count, diabetes, and hypertension, whereas LF was associated with previous exposure to dideoxynucleoside drugs and current CD4 to LF. Current integrase strand transfer inhibitor (INSTI) therapy appeared protective for LF in cohort 1. In this study, one in four people with HIV had LS, and the prevalence rose to one in two in those with cardiovascular risk factors. The prevalence of LF was low, but it should be considered in older people with HIV with low CD4 counts or high aspartate transaminase levels. A possible protective effect from INSTIs deserves further investigation.

Diagnostic and prognostic value of plasma lipocalin-2 levels in patients with metabolic dysfunction–associated steatotic liver disease

Abstract Background Non-Alcoholic Fatty Liver Disease, recently better recognised as Metabolic Dysfunction–Associated Steatotic Liver Disease, is the most prevalent form of chronic liver disease at present time. It is estimated to impact 32% of the world's population, hence representing a significant health burden. Aim of the work To assess the significance of plasma Lipocalin-2 (LCN2) levels in the diagnosis and prognosis of NAFLD patients. Patients and methods In this retrospective case–control study we recruited 102 subjects aged between 18 and 70 years. The included participants were split into two study groups. Group I: 51 NAFLD patients (61% men, 39% females) and Group II: 51 healthy controls (51% men and 49% females), for whom plasma LCN2 levels were assessed and correlated with NAFLD fibrosis score, FIB4 and fatty liver index. Results In this study, LCN2 levels in NAFLD patients were significantly greater compared to individuals in the control group (p &lt; 0.001), with a mean of 1893.214 ± 1002.852 ng/dL in the cases and a mean of 466.020 ± 397.699 ng/dL in the controls. This suggests the use of LCN2 as a possible diagnostic marker of NAFLD. The mean LCN2 levels in this study also significantly increased as the grade of fatty liver increased from I to III (p &lt; 0.001). This in turn proposes the use of LCN2 as a prognostic marker for NAFLD progression. LCN2 also significantly correlated with the fatty liver index and NAFLD Fibrosis scoring systems, but not with Fib-4. With an area under the ROC of 0.906, it demonstrated excellent diagnostic performance with 84% sensitivity, 90% specificity, 89.6% PPV and 85.2% NPV for the prediction of NAFLD patients. Conclusion Lipocalin-2 performs as a diagnostic and a possible prognostic marker for metabolic dysfunction-associated steatotic liver disease.

A direct comparison of non-invasive blood markers of liver fibrosis as associates of cardiovascular risk. The Athens cardiometabolic registry

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is associated with increased risk of cardiovascular disease (CVD). This risk increases further with advanced liver fibrosis. To date, non-invasive tests (NIT) for liver fibrosis risk have not been established as diagnostic or prognostic biomarkers of CVD. Purpose The purpose of the study was to compare NIT of liver fibrosis with respect to their associations with vascular injury and cardiovascular (CV) events. Methods Individuals without clinically overt CVD and patients with CVD (total n=1,692), consecutively recruited in the Athens Cardiometabolic Registry, were analysed in this study. We retrospectively evaluated the association of NIT (i.e. Fibrosis-4 index (FIB-4), NAFLD Fibrosis score (NFS), BARD score) with indices of subclinical arterial injury (i.e. carotid wall thickness and atherosclerotic plaque for subclinical atherosclerosis, pulse wave velocity (PWV), for arterial stiffness) and the incidence of CV events. Patients were followed-up for CV events for a median time of 39 months. Results Elevated FIB-4 (&amp;gt;2.67) was associated with vascular damage [adjusted odds ratio (aOR)=2.97, 95% confidence intervals (CI)= 1.71-5.78 for maximal wall thickness (maxWT) and aOR=4.58, 95% CI=2.44-8.60 for PWV] across the entire study population, including those with or without clinically overt CVD. NFS&amp;gt; 0.675 showed similar associations but lacked significant correlation with arterial stiffness in coronary artery disease patients. FIB-4&amp;gt; 2.67 and BARD&amp;gt; 2 were associated with increased risk of the composite endpoint of CV death, acute myocardial infarction, or coronary revascularization [adjusted hazard ratio, (aHR)=2.00, 95% CI= 1.12-3.55 and aHR=3.36, 95% CI=1.03-11.0 for FIB-4 (n=842) and BARD (n=887) respectively]. FIB-4 and BARD as continuous variables confered incremental prognostic value compared to European Systematic Coronary Risk Evaluation 2 (SCORE2). Conclusion In a population with a wide range of cardiometabolic risk, FIB-4 was associated with both markers of atherosclerotic disease and arterial stiffness as well as with adverse CV events. These data support further investigation of FIB-4 as a biomarker of CV risk.

Effects of sodium-glucose contrasporter-2 inhibitors and glucagon-like peptide-1 receptor agonists on arterial stiffness, coronary flow reserve and liver steatosis in diabetes

Abstract Background Patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) present an increased risk of cardiovascular disease. Sodium-glucose contrasporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to significantly decrease the risk of cardiovascular complications. Purpose The aim of the study was to investigate the effect of treatment with SGLT-2i or GLP-1RA on cardiovascular function and liver steatosis and fibrosis in patients with T2DM and NAFLD. Methods Forty patients with T2DM and NAFLD (mean age: 58 ± 11 years) were randomized to receive SGLT-2i (dapagliflozin; n = 20) or GLP-1RA (dulaglutide; n = 20). At baseline and after 6 and 12 months of treatment, we measured: (1) perfused boundary region (PBR) of the sublingual microvessels with a diameter 5-25μm using Sidestream Dark Field camera (Microscan, Glycocheck). Increased PBR indicates reduced glycocalyx thickness. (2) Pulse wave velocity (PWV) using Complior (ALAM Medical), (3) coronary flow reserve (CFR) using Doppler echocardiography, (4) LV global longitudinal strain (GLS) using speckle-tracking echocardiography, (5) controlled attenuation parameter (CAP) score to assess steatosis grade and liver stiffness (E) to evaluate fibrosis score using liver elastography (FibroScan, Echosens), and (6) NAFLD fibrosis score (NFS). Results At baseline, patients between the two groups had similar age, sex, HbA1c, steatosis grade, fibrosis score and markers of cardiovascular function (p &amp;gt; 0.05). Compared with baseline, all patients had reduced PBR, PWV, CAP, E and NFS and increased CFR and GLS (p &amp;lt; 0.01) after 12-month treatment. In the whole study population, the percentage reduction of CAP and NFS was correlated with the corresponding decrease of PBR (r = 0.248 and r = 0.387), PWV (r = 0.290 and r = 0.281) and with the increase of GLS (r = -0.320 and r = -0.295) after 12-month treatment (p &amp;lt; 0.05 for all correlations). Both treatments with SGLT-2i and GLP-1RA reduced markers of liver steatosis and fibrosis (Table). Conclusion Both treatments with SGLT-2i and GLP-1RA improve cardiovascular function and reduce liver steatosis in patients with T2DM and NAFLD after 12 months.

DII modulates the relationship between SVD3 and NAFLD prevalence, rather than liver fibrosis severity, in hospitalized T2DM population

Type 2 diabetes (T2DM) patients are at high risk for non-alcoholic fatty liver disease (NAFLD). Studies show SVD3 and dietary inflammatory index (DII) are associated with NAFLD. It’s unknown if they interact in T2DM patients with NAFLD. We collected data from 110 hospitalized T2DM patients, measured physiological and biochemical indicators, conducted dietary surveys, and converted data into DII and NFS, FIB-4, and BARD indices. We used logistic regression, mediation effect analysis, and moderation effect analysis to explore the relationship between DII and SVD3 with NAFLD and liver fibrosis in T2DM patients. DII was not significant in either NAFLD incidence in T2DM patients or liver fibrosis in NAFLD patients. SVD3 was positively correlated with NAFLD incidence in T2DM patients, but this correlation became insignificant as DII increased towards pro-inflammation. SVD3 is positively correlated with NAFLD incidence in T2DM patients, but this correlation becomes less significant as DII increases towards pro-inflammation.

Diagnostic role of the fibrosis-4 index and nonalcoholic fatty liver disease fibrosis score as a noninvasive tool for liver fibrosis scoring.

Nonalcoholic fatty liver disease (NAFLD) is characterized by liver fibrosis, which serves as a crucial indicator of its progression and prognosis. Owing to the limitations of biopsy, which is the gold standard for measuring liver fibrosis, a reliable and noninvasive marker is required. We evaluated the diagnostic role of the fibrosis-4 (FIB-4) index and nonalcoholic fatty liver disease fibrosis score (NFS) in patients with NAFLD with varying severities of liver fibrosis. The FIB-4 index and NFS were calculated using laboratory data from 121 patients who underwent liver biopsies between January 2022 and December 2023. The results were compared with those of the Scheuer scoring system for liver biopsies (F0, F1 + F2, and F3 + F4) to determine the sensitivity and specificity of the FIB-4 index and the liver disease fibrosis score in detecting and staging liver fibrosis. Twenty-one patients had advanced fibrosis (F3-F4), and 100 had minimal or mild fibrosis (F0-F2). The degree of liver fibrosis increased with decreased albumin, alanine aminotransferase and platelet count levels, and increasing age. Receiver operating characteristic curve analysis for the FIB-4 index and NFS revealed that the areas under the curve for the FIB-4 index and NFS were 0.895 (95% confidence interval: 0.836-0.954) and 0.882 (95% confidence interval: 0.813-0.952), respectively. The FIB-4 indices showed 95.24% sensitivity at a cutoff point of 1.30, and 85% specificity at a cutoff point of 2.67, while the NFS indices showed 95.24% sensitivity at -1.455 cutoff point and 95% specificity at a cutoff point of 0.676. The FIB-4 index and NFS may replace biopsy for the detection of fibrosis in patients with NAFLD.

The Effect of Biologic Agents on Steatotic Liver Disease in Patients with Inflammatory Bowel Disease: A Prospective, Open-Label Comparative Trial.

Biologic agents used in patients with inflammatory bowel diseases (IBD) may influence the pathophysiology of coexistent metabolic-dysfunction associated steatotic liver disease (MASLD). This study primarily aimed to evaluate the six-month effect of infliximab or vedolizumab vs. no biologics on presumed hepatic steatosis in patients with IBD. Secondary endpoints were their effect on hepatic fibrosis and parameters related to hepatic metabolism. This prospective, non-randomized, controlled trial assigned adult bio-naïve patients with IBD into three groups: infliximab, vedolizumab, or controls (receiving no biologic). The baseline was the time of the initiation of biologic agents and the endpoint six months later. Hepatic steatosis was evaluated with transabdominal ultrasonography (Hamaguchi score), whereas controlled attenuation parameter (CAP), fatty liver index (FLI), and hepatic steatosis index (HSI) were used as surrogates. Hepatic fibrosis was evaluated with liver stiffness (LS), fibrosis-4 index (FIB-4), and nonalcoholic fatty liver disease (NAFLD) fibrosis score. Sixty-six patients were assigned to infliximab (n = 26), vedolizumab (n = 14), or control (n = 26); At the endpoint, the Hamaguchi score, CAP, FLI, and HSI were not different between groups. LS was not different between groups; however, FIB-4 was increased within all groups, and NAFLD fibrosis score was increased within infliximab and control groups, without significant biologic × time interactions. No positive or adverse effect of infliximab or vedolizumab vs. no biologic agents was shown on presumed hepatic steatosis in patients with IBD, who have not been previously exposed to biologic agents. Although no effect of both biologic agent on LS, a slight but significant increase in FIB-4 and NAFLD fibrosis score warrants further studying.

Implementation of Machine Learning Algorithms to Screen for Advanced Liver Fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease: An In-Depth Explanatory Analysis.

This study aimed to train machine learning algorithms (MLAs) to detect advanced fibrosis (AF) in metabolic dysfunction-associated steatotic liver disease (MASLD) patients at the level of primary care setting and to explain the predictions to ensure responsible use by clinicians. Readily available features of 618 MASLD patients followed up at a tertiary center were used to train five MLAs. AF was defined as liver stiffness ≥9.3 kPa, measured via 2-dimension shear wave elastography (n = 495) or liver biopsy ≥F3 (n = 123). MLAs were compared to Fibrosis-4 index (FIB-4) and non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) on 540 MASLD patients from the primary care setting as validation. Feature importance, partial dependence, and shapely additive explanations (SHAPs) were utilized for explanation. Extreme gradient boosting (XGBoost) achieved an AUC = 0.91, outperforming FIB-4 (AUC = 0.78) and NFS (AUC = 0.81, both p < 0.05) with specificity = 76% versus 59% and 48% for FIB-4 ≥1.3 and NFS ≥-1.45, respectively (p < 0.05). Its sensitivity (91%) was superior to FIB-4 (79%). XGBoost confidently excluded AF (negative predictive value = 99%) with the highest positive predictive value (31%), superior to FIB-4 and NFS (all p < 0.05). The most important features were HbA1c and gamma glutamyl transpeptidase (GGT) with a steep increase in AF probability at HbA1c >6.5%. The strongest interaction was between AST and age. XGBoost, but not logistic regression, extracted informative patterns from ALT, low-density lipoprotein cholesterol, and alkaline phosphatase (p < 0.001). One-quarter of the false positives (FPs) were correctly reclassified with only one additional false negative based on the SHAP values of GGT, platelets, and ALT which were found to be associated with a FP classification. An explainable XGBoost algorithm was demonstrated superior to FIB-4 and NFS for screening of AF in MASLD patients at the primary care setting. The algorithm also proved safe for use as clinicians can understand the predictions and flag FP classifications.

Bovine Lactoferrin Mitigates Oxidative Stress and Inflammation in CCL4 and High-fat Diet-induced NAFLD in C57BL/6 Mice

Background: Impacting approximately 20-30% of adults, nonalcoholic fatty liver disease (NAFLD) is the leading contributor to liver dysfunction. This condition is characterized by the accumulation of more than 5% fat in the liver without the presence of concurrent chronic liver diseases or alcohol abuse. NAFLD manifests across a spectrum ranging from simple steatosis to more complex forms involving hepatic lesions, inflammation and fibrosis. This research aimed to assess the therapeutic effectiveness of Bovine Lactoferrin (BLF) in a model of NAFLD using male C57BL/6 mice. Methods: Adult male C57BL6 mice, with an average weight of 28 g, were obtained and maintained in a consistent environment at 22±2oC for 6 weeks, following a regulated 12-hour light-12-hour dark cycle. Control groups 1 and 3 were provided with a standard pellet feed, while model groups 2, 4, 5 and 6 were supplied with a high-fat diet. Induction of NAFLD included administering a high-fat diet (HFD) and CCl4 (0.5 mg/kg with olive oil) twice a week via intraperitoneal injection over 6 weeks. After the experimental procedures, an assessment of serum-biochemical parameters, inflammatory cytokines, anti-oxidant profile and liver histopathology were conducted. Result: The results revealed significant (p less than 0.05) alteration in sero-biochemical parameters, inflammatory cytokines (IL-10, TNF-α, NF-kB and TGF-β) anti-oxidant profile (nitric oxide assay, TBARS, SOD, GSH and Catalase) and histopathology of group 2 as compared to other groups. The groups 4, 5 and 6 showed significant improvement in all the parameters compared to disease control. The findings from this study suggest that BLF could potentially function as a therapeutic intervention for mitigating hepatic injury, inflammation and fibrosis in NAFLD by deactivating NF-kB pathway.

Association between Body Fat Distribution and Nonalcoholic Fatty Liver Disease/Fibrosis Based on Race/Ethnicity.

Body fat distribution may impact nonalcoholic fatty liver disease (NAFLD) and significant fibrosis differently according to race/ethnicity. We determined the relationship between body fat distribution and NAFLD/significant fibrosis according to race/ethnicity. A cross-sectional study of 2,395 participants used the National Health and Nutrition Examination Survey 2017 to 2018. NAFLD and significant fibrosis (≥F2) were defined by controlled attenuation parameter scores and liver stiffness measurements on transient elastography, respectively. Visceral and subcutaneous fat volumes were defined by dual-energy X-ray absorptiometry. The odds ratio (OR) for NAFLD per 1-standard deviation in visceral fat volume and subcutaneous fat volume was 2.31 (95% confidence interval [CI], 1.50 to 3.39) and 1.93 (95% CI, 1.43 to 2.61) in total population, respectively. Visceral fat in non-Hispanic Blacks had the highest odds for NAFLD (OR, 2.86; 95% CI, 1.45 to 5.62), and non-Hispanic Whites (OR, 2.29; 95% CI, 1.19 to 4.40) and non-Hispanic Asians (OR, 1.61; 95% CI, 1.13 to 2.29) were in order. Significant associations between subcutaneous fat volume (OR, 2.10; 95% CI, 1.34 to 3.29; P=0.003) or visceral fat volume (OR, 1.35; 95% CI, 1.05 to 1.73; P=0.023) and significant fibrosis were noted among individuals with NAFLD. Hispanics had the highest odds for NAFLD-associated significant fibrosis (OR, 2.74; 95% CI, 1.32 to 5.70), and non-Hispanic Whites (OR, 2.35; 95% CI, 1.11 to 4.98) and non-Hispanic Asians (OR, 2.01; 95% CI, 1.01 to 4.01) were in order. Visceral adiposity was associated with NAFLD and significant fibrosis despite the association of subcutaneous adiposity in NAFLD and significant fibrosis. Racial/ethnic differences in the association between body fat distribution on NAFLD and significant fibrosis were noted.

Elevated non-HDL-C to HDL-C ratio as a marker for NAFLD and liver fibrosis risk: a cross-sectional analysis.

Dyslipidemia is a known independent risk factor for Nonalcoholic fatty liver disease (NAFLD). However, the relationship between NAFLD and the serum non-high-density lipoprotein cholesterol (non-HDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio remains unclear. This study examined the association between the non-HDL-C to HDL-C ratio and NAFLD prevalence, including liver steatosis and fibrosis levels in the population. We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018, including 4798 participants. Liver ultrasound and Transient Elastography (TE) were used to assess fibrosis and steatosis. Adjusted multivariable regression analyses, subgroup analyses based on BMI and sex, and a generalized additive model were employed to investigate the relationship between the non-HDL-C/HDL-C ratio and NAFLD. Among the 4798 participants, 39.27% (n = 1,884) had NAFLD. Significant positive correlations between non-HDL-C/HDL-C and NAFLD risk were found across all models, with sex-stratified analyses indicating higher risk in men. Liver fibrosis was also associated with non-HDL-C/HDL-C ratios. The Receiver operating characteristic (ROC) analysis shows non-HDL-C/HDL-C as a better predictor for NAFLD than non-HDL-C or HDL-C alone. Elevated non-HDL-C/HDL-C levels are independently associated with increased NAFLD and liver fibrosis risk in the American population, suggesting its utility in predicting NAFLD and related liver fibrosis.