Background and Aims: Screening for liver fibrosis presents a clinical challenge. This study aimed to explore a useful alternative method for assessing fibrosis risk among US adults at risk of metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: A liver stiffness score (LSS) model was proposed and tested using data from 3976 participants at possible risk of MASLD, obtained from the US National Health and Nutrition Examination Survey (NHANES). Results: The LSS model was developed using liver stiffness measurements, blood biochemistry, and body measurement data from 2414 NHANES participants at risk of MASLD, sampled between 2017 and 2020: LSS = exp(0.007035 × bodyweightkg - 0.1061 × raceblack1,0 + 0.183221 × diabetes1,0 + 0.008539 × ASTIU/L - 0.0018 × plateletcount1000cell/UL - 0.21011 × albuming/dL + 2.259087). The probability (P) of having fibrosis F3 + F4 is calculated as follows: P = 0.0091 × LSS2 - 0.0791 × LSS + 0.1933. The developed LSS model was tested on 1562 at-risk participants from the 2017-2018 cycle. The results showed that the LSS model achieved AUROC values of 0.79 and 0.78 for diagnosing cirrhosis (F4) and advanced fibrosis (F3 + F4) in the US population, respectively. It outperformed existing models such as NFS, FIB-4, SAFE, and FIB-3. For screening F3 + F4 fibrosis, the LSS model\'s top decile outperformed the NFS and FIB-4 models by 37.7% and 42.6%, respectively. Additionally, it showed superior performance compared to the waist circumference classification method by 29.5%. Conclusions: derived from an ethnically diverse population dataset, the LSS screening model, along with its probability equation, may offer clinicians a valuable alternative method for assessing the risk of liver fibrosis in the at-risk adult population.

UNASSIGNED: The impact of chronic hepatic infection on antigen non-specific immune cells in circulation remains poorly understood. We reported lasting global hyperfunction of peripheral CD8 T cells in HCV-infected individuals with cirrhosis. Whether gene expression patterns in bulk CD8 T cells are associated with the severity of liver fibrosis in HCV infection is not known.
UNASSIGNED: RNA sequencing of blood CD8 T cells from treatment naïve, HCV-infected individuals with minimal (Metavir F0-1 ≤ 7.0 kPa) or advanced fibrosis or cirrhosis (F4 ≥ 12.5 kPa), before and after direct-acting antiviral therapy, was performed. CD8 T cell function was assessed by flow cytometry.
UNASSIGNED: In CD8 T cells from pre-DAA patients with advanced compared to minimal fibrosis, Gene Ontology analysis and Gene Set Enrichment Analysis identified differential gene expression related to cellular function and metabolism, including upregulated Hedgehog (Hh) signaling, IFN-α, -γ, TGF-β response genes, apoptosis, apical surface pathways, phospholipase signaling, phosphatidyl-choline/inositol activity, and second-messenger-mediated signaling. In contrast, genes in pathways associated with nuclear processes, RNA transport, cytoskeletal dynamics, cMyc/E2F regulation, oxidative phosphorylation, and mTOR signaling, were reduced. Hh signaling pathway was the top featured gene set upregulated in cirrhotics, wherein hallmark genes GLI1 and PTCH1 ranked highly. Inhibition of Smo-dependent Hh signaling ablated the expression of IFN-γ and perforin in stimulated CD8 T cells from chronic HCV-infected patients with advanced compared to minimal fibrosis. CD8 T cell gene expression profiles post-DAA remained clustered with pre-DAA profiles and disparately between advanced and minimal fibrosis, suggesting a persistent perturbation of gene expression long after viral clearance.
UNASSIGNED: This analysis of bulk CD8 T cell gene expression in chronic HCV infection suggests considerable reprogramming of the CD8 T cell pool in the cirrhotic state. Increased Hh signaling in cirrhosis may contribute to generalized CD8 T cell hyperfunction observed in chronic HCV infection. Understanding the lasting nature of immune cell dysfunction may help mitigate remaining clinical challenges after HCV clearance and more generally, improve long term outcomes for individuals with severe liver disease.

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BACKGROUND: Effective screening for alcohol-associated liver disease is relevant in the context of chronic, excessive alcohol consumption. Patients with alcohol-associated liver disease are often not diagnosed until their liver disease is decompensated. We analyzed the prevalence and associations of Fibrosis-4 index (FIB-4) values suggestive of advanced liver fibrosis in patients referred for their first treatment of alcohol use disorder (AUD).
METHODS: We conducted a cross-sectional, multicenter study of noncirrhotic individuals referred for their first AUD treatment between March 2013 and April 2021. We obtained sociodemographic data, substance use characteristics, and blood samples at admission. We considered a FIB-4 value ≥2.67 suggestive of advanced liver fibrosis and used logistic regression analyses to identify features associated with this value.
RESULTS: We included 604 patients (67% male), with a median age at admission of 48 years [IQR: 41-56 years]. The median duration of regular alcohol consumption was 21 years [IQR: 18-30 years] and the median alcohol consumption was 105 standard drink units (SDU)/week [IQR: 63-160 SDU/week]. A FIB-4 value ≥ 2.67 was present in 19.3% of cases. These patients reported more frequent binge drinking (75.4% vs. 66%, p = 0.05) than those with FIB-4 values below 2.67. In multivariate analysis, a history of binge drinking (OR 1.9, 95% CI, 1.05-3.47), anemia (OR 2.95, 95% CI, 1.42-6.11), leukopenia (OR 7.46, 95% CI, 2.07-26.8), and total serum bilirubin >1 mg/dL (OR 6.46, 95% CI, 3.57-11.7) were independently associated with FIB-4 values ≥2.67.
CONCLUSIONS: One in five patients admitted to treatment for AUD without evidence of decompensated liver disease have FIB-4 values suggestive of advanced liver fibrosis. The presence of a binge drinking history, anemia, leukopenia, and elevated bilirubin levels is associated with high FIB-4 values.

BACKGROUND: Vitamin D deficiency is a risk factor for liver disease, insulin resistance, and beta cell dysfunction. Individuals with alcohol use disorder (AUD) have many comorbidities, with a heavy burden of liver disease and metabolic complications, including type 2 diabetes mellitus (T2DM).
OBJECTIVE: We aimed to analyze the prevalence and associations of vitamin D deficiency in patients admitted for in-hospital treatment of AUD.
METHODS: A cross-sectional study was conducted in patients consecutively admitted for the treatment of AUD between January 2017 and October 2023. Sociodemographic data, substance use characteristics, and blood parameters were available at admission. Vitamin D status was assessed through the serum concentrations of 25-hydroxyvitamin D [25(OH)D] levels using a direct competitive chemiluminescent immunoassay method. Deficiency of vitamin D was defined as a concentration less than 20 ng/mL; impaired fasting glucose (IFG) was defined by fasting blood glucose >100 mg/dL (5.6 mmol/L), and advanced liver fibrosis by an FIB-4 index >3.25.
RESULTS: Two hundred and forty-three patients were included (75% male) with a mean age of 49 ± 10 years, mean BMI of 26.4 ± 7.3, mean alcohol consumption of 163 ± 81 g/day, and a mean duration of AUD of 18.1 ± 11.2 years. Mean 25(OH)D, fasting blood glucose, AST, ALT, and platelets were 14.4 ± 10.2 ng/mL, 103.4 ± 40.9 mg/dL, 55.1 ± 75.8 U/L, 44.8 ± 76.6 U/L, and 206.3 ± 84.8 × 109/L, respectively. The prevalence of vitamin D deficiency was 80.6%, and 41.1% of patients had levels less than 10 ng/mL. IFG was present in 32.3% of patients, and 20.5% had FIB-4 values >3.25. In the multivariable analysis, IFG (OR, 2.51; 95% CI: 1.02-6.17, p = 0.04) and advanced liver fibrosis (OR, 4.27; 95% CI: 1.21-15.0, p = 0.02) were the only factors associated with vitamin D deficiency.
CONCLUSIONS: Vitamin D deficiency was very prevalent in this series of patients with AUD and was associated with impaired fasting glucose and advanced liver fibrosis.

UNASSIGNED: This study explored the potential association between the Prognostic Nutritional Index (PNI) and the incidence of non-alcoholic fatty liver disease (NAFLD) and advanced liver fibrosis (AF) in the adult population of the United States.
UNASSIGNED: Information on 6409 participants ≥18 years old was downloaded from the U.S. National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020. Multivariate analysis was combined with demographic factors to assess the relationships between PNI, NAFLD, and AF. A restricted cubic spline (RCS) was used to characterise the nonlinear association between the PNI and NAFLD and AF.
UNASSIGNED: Patients without NAFLD had substantially lower mean values for parameters such as age, lymphocyte count, neutrophil count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammatory index (SII), total cholesterol, triglycerides, HbA1c, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) than patients with NAFLD. Interestingly, non-NAFLD patients showed a pronounced increase in serum albumin levels compared to their NAFLD counterparts. In the subset without AF, there were discernibly lower measures of NLR, age, AST, ALT, γ-glutamyl transferase, triglycerides, neutrophil count, and body mass index (BMI) than in patients with AF. It was evident that those without AF had markedly elevated mean albumin and PNI levels in comparison to AF-affected individuals. In the comprehensive multivariable framework, a direct correlation was observed between PNI and NAFLD (adjusted odds ratio[aOR] = 1.07, 95% confidence interval [CI]: 1.05-1.09; p < 0.001), whereas PNI and AF were inversely correlated (aOR = 0.92; 95% CI: 0.88-0.96; p < 0.001). Within the RCS model, a swift ascendancy was noted in the relationship between the PNI and NAFLD, peaking at approximately 52. Conversely, a non-linear inverse association was observed between PNI and AF.
UNASSIGNED: Our analytical results indicate that elevated PNI levels are positively associated with an increased risk of NAFLD, but inversely related to the risk of AF. For robust validation of these observations, further research is required.

Copper functions as an essential micronutrient influencing diverse metabolic processes in mammals, encompassing oxidative stress responses, lipid metabolism, and participation in enzymatic reactions. However, the impact of serum copper on non-alcoholic fatty liver disease (NAFLD) remains controversial. Our aim was to explore the precise correlation between serum copper and NAFLD in a large-scale population-based study. A total of 1377 participants from the National Health and Nutrition Examination Survey (NHANES) 2011-2016 were included in our study. The diagnosis of NAFLD and its progress to advanced liver fibrosis were based on serological indexes. One-way ANOVA, Kruskal-Wallis H test, and Chi-square test were used to access variations between quartiles groups of serum copper. We conducted multivariate-adjusted logistic regression models and subgroup analyses to investigate the association between serum copper and NAFLD, along with several metabolic diseases. Among the 1377 participants, 661 were diagnosed with NAFLD, and 141 of whom were classified into advanced liver fibrosis. Higher serum copper levels (≥ 21.00 μmol/L) were associated with an increased incidence of NAFLD (odds ratio (OR) = 2.07 (1.38-3.10), p < 0.001), as well as advanced liver fibrosis (OR = 2.40 (1.17-5.19), p = 0.025). Moreover, serum copper exhibited a positive correlation with hypertension, overweight, and abdominal obesity, all of which have been identified as risk factors of NAFLD. Additionally, female participants, under the age of 60, and with a higher body mass index (BMI) (> 24.9 kg/m2) emerged as the most vulnerable subgroup concerning the relationship between serum copper and NAFLD. In the U.S. population, a notable association has been identified, linking elevated serum copper to an increased susceptibility for both the onset and progression of NAFLD, along with several metabolic disorders associated with NAFLD. The adverse effects of excess copper warrant attention in the context of public health considerations.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, and liver fibrosis is the strongest predictor of morbimortality. We aimed to assess the performance of a sequential algorithm encompassing the Fibrosis 4 (FIB-4) and Enhanced Liver Fibrosis (ELF) scores for identifying patients at risk of advanced fibrosis. This cross-sectional study included one hospital-based cohort with biopsy-proven NAFLD (n = 140) and two primary care cohorts from different clinical settings: Type 2 Diabetes (T2D) follow-up (n = 141) and chronic liver disease (CLD) initial study (n = 138). Logistic regression analysis was performed to assess liver fibrosis diagnosis models based on FIB-4 and ELF biomarkers. The sequential algorithm retrieved the following accuracy parameters in predicting stages F3-4 in the biopsy-confirmed cohort: sensitivity (85%), specificity (73%), negative predictive value (79%) and positive predictive value (81%). In both T2D and CLD cohorts, a total of 28% of patients were classified as stages F3-4. Furthermore, of all F3-4 classified patients in the T2D cohort, 80% had a diagnosis of liver disease and 44% were referred to secondary care. Likewise, of all F3-4 classified patients in the CLD cohort, 71% had a diagnosis of liver disease and 44% were referred to secondary care. These results suggest the potential utility of this algorithm as a liver fibrosis stratifying tool in primary care, where updating referral protocols to detect high-risk F3-4 is needed. FIB-4 and ELF sequential measurement is an efficient strategy to prioritize patients with high risk of F3-4 in populations with metabolic risk factors.

We aimed to investigate the association between air pollution and advanced fibrosis among patients with metabolic associated fatty liver disease (MAFLD) and chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. A total of 1376 participants who were seropositive for HBV surface antigen (HBsAg) or antibodies to HCV (anti-HCV) or had abnormal liver function in a community screening program from 2019 to 2021 were enrolled for the assessment of liver fibrosis using transient elastography. Daily estimates of air pollutants (particulate matter ≤2.5 μm in diameter [PM2.5 ], nitrogen dioxide [NO2 ], ozone [O3 ] and benzene) were aggregated into mean estimates for the previous year based on the date of enrolment. Of the 1376 participants, 767 (52.8%) and 187 (13.6) had MAFLD and advanced fibrosis, respectively. A logistic regression analysis revealed that the factors associated with advanced liver fibrosis were HCV viremia (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.05-4.77; p < 0.001), smoking (OR, 1.79; 95% CI, 1.16-2.74; p = 0.01), age (OR, 1.04; 95% CI, 1.02-1.05; p < 0.001) and PM2.5 (OR, 1.10; 95% CI, 1.05-1.16; p < 0.001). Linear regression analysis revealed that LSM was independently correlated with PM2.5 (β: 0.134; 95% CI: 0.025, 0.243; p = 0.02). There was a dose-dependent relationship between different fibrotic stages and the PM2.5 level (the PM2.5 level in patients with fibrotic stages 0, 1-2 and 3-4: 27.9, 28.4, and 29.3 μg/m3 , respectively; trend p < 0.001). Exposure to PM2.5 , as well as HBV and HCV infections, is associated with advanced liver fibrosis in patients with MAFLD. There was a dose-dependent correlation between PM2.5 levels and the severity of hepatic fibrosis.

Heart failure with preserved ejection fraction (HFpEF), a major cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM), is frequently coexisted with obesity, poor glycemic, blood pressure (BP), and/or lipid control. We aimed to investigate the associations of nonalcoholic fatty liver disease (NAFLD) and its advanced fibrosis with HFpEF according to obesity, glycated hemoglobin A1c (HbA1c), BP, and low-density lipoprotein cholesterol (LDL-C) goal achievement status in T2DM patients.
A total of 2,418 T2DM patients who were hospitalized were cross-sectionally assessed. Liver fibrosis was evaluated by non-invasive biomarkers. Logistic regression analysis was used to evaluate the independent and combined associations of fibrosis status and diabetic care goal attainments with HFpEF risk.
Simple steatosis was not associated with HFpEF risk compared with patients without steatosis, while advanced liver fibrosis was found to have significantly higher odds for HFpEF risk (odds ratio,1.59; 95% confidence interval, 1.22-2.08). Advanced fibrosis in NAFLD was significantly associated with an increased risk of HFpEF, regardless of obesity status, HbA1c, BP, and LDL-C goal achievement status. P values for the interactions between fibrosis status and HbA1c control status, fibrosis status and BP control status, fibrosis status and LDL-C control status, and fibrosis status and body mass index (BMI) status on HFpEF risk were 0.021, 0.13, 0.001, and 0.23, respectively.
In patients with T2DM, advanced hepatic fibrosis was significantly associated with HFpEF risk, irrespective of obesity status, HbA1c, BP, and LDL-C goal attainment status. Further, HbA1c and LDL-C goal attainment status modified this association.