This study aimed to investigate the association between the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and NAFLD, as well as its relationship with hepatic steatosis and liver fibrosis, in a nationally representative sample of U.S. adults.

This cross-sectional study analyzed data from 3,529 participants from the National Health and Nutrition Examination Survey in 2017-2020. Multivariable logistic regression and subgroup analyses were used to assess the association between NHHR and NAFLD. Multivariate linear regression was employed to evaluate the relationship between NHHR and hepatic steatosis (controlled attenuation parameter) and liver fibrosis (liver stiffness measurement). Nonlinear relationships were explored through fitted smoothing curves and threshold effect analysis. Receiver operating curve (ROC) analysis was performed to compare the diagnostic performance of NHHR with body mass index (BMI), high-density lipoprotein cholesterol (HDL-C), and total cholesterol (TC).

The study included 3,529 participants (mean age: 51.34 years, 95% CI: 49.97, 52.72), with 53.53% male. NHHR showed a significant positive association with NAFLD after adjusting for confounders (OR: 1.33, 95% CI: 1.24, 1.42). Subgroup analysis indicated a stronger association in females and individuals with normal weight. A nonlinear relationship was identified, with a significant positive association below an inflection point of 4 (OR: 1.52, 95% CI: 1.38, 1.68). NHHR was positively associated with hepatic steatosis but not with liver fibrosis. For NAFLD diagnosis, NHHR achieved an area under the curve (AUC) of 0.66, outperforming TC (AUC = 0.51) but indicating lower accuracy than BMI (AUC = 0.77) and HDL-C (AUC = 0.68).

NHHR is positively associated with NAFLD and hepatic steatosis in U.S. population, highlighting the important role of lipid control in the prevention and clinical management of NAFLD.

Non-alcoholic (now: metabolic) steatohepatitis (MASH) is the progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD), which often coexists and mutually interacts with type 2 diabetes (T2D), resulting in worse hepatic and cardiovascular outcomes. Understanding the intricate mechanisms of diabetes-related MASH progression is crucial for effective therapeutic strategies. This review delineates the multifaceted pathways involved in this interplay and explores potential therapeutic implications. The synergy between adipose tissue, gut microbiota, and hepatic alterations plays a pivotal role in disease progression. Adipose tissue dysfunction, particularly in the visceral depot, coupled with dysbiosis in the gut microbiota, exacerbates hepatic injury and insulin resistance. Hepatic lipid accumulation, oxidative stress, and endoplasmic reticulum stress further potentiate inflammation and fibrosis, contributing to disease severity. Dietary modification with weight reduction and exercise prove crucial in managing T2D-related MASH. Additionally, various well-known but also novel anti-hyperglycemic medications exhibit potential in reducing liver lipid content and, in some cases, improving MASH histology. Therapies targeting incretin receptors show promise in managing T2D-related MASH, while thyroid hormone receptor-β agonism has proven effective as a treatment of MASH and fibrosis.

Although recombinant tissue plasminogen activator (rt-PA) treatment is efficient in patients with acute ischemic stroke (AIS), a significant percentage of patients who received rt-PA intravenous thrombolysis (IVT) do not achieve a good prognosis. Therefore, the factors that affect the poor prognosis of patients with IVT are needed. The Fibrosis-4 (FIB-4) index has been used as a liver fibrosis biomarker. We aimed to investigate the relationship between the FIB-4 index and functional outcomes in patients with AIS receiving IVT.

This study prospectively included consecutive patients with AIS receiving IVT between April 2015 and May 2022. We collected clinical and laboratory data and calculated the FIB-4 index. Clinical outcome was poor functional outcome (mRS ≥3) at 3 months after IVT. Multivariate logistic regression analysis was used to analyze the association between FIB-4 and outcome. We explored the interactive effect of FIB-4 and dyslipidemia on poor outcomes, and subgroup analysis was performed. Furthermore, an individualized prediction model based on the FIB-4 for functional outcome was established in the dyslipidemia group.

A total of 1135 patients were included, and 41.50% had poor 3-month outcomes. After adjusted by other variants that P value <0.05 in univariable analysis, FIB-4 was independently associated with poor outcomes (OR=1.420; 95% CI: 1.113-1.812; P=0.004). There was a significant interaction between FIB-4 and dyslipidemia on poor outcome (P=0.036), and the independent association between FIB-4 and poor outcome was maintained in the dyslipidemia subgroup (OR=1.646; 95% CI: 1.228-2.206; P=0.001). Furthermore, in the dyslipidemia group, the FIB-4-based prediction model had good predictive value (the AUC of the training and validation sets were 0.767 and 0.708, respectively), good calibration (P-values for the Hosmer-Lemeshow test >0.05), and clinical usefulness.

FIB-4 is an independent risk factor for poor outcomes in IVT patients with dyslipidemia, which can be used as a simple predictor of their prognosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) brings heavy clinical and economic burdens to patients worldwide. High fasting plasma glucose (HFPG) was proven to be an important modifiable risk factor. However, the global burden distribution of HFPG-attributable MASLD has not been fully studied. This study aimed to describe the epidemiological distribution and trends of the burden of HFPG-attributable MASLD worldwide. The data source was the 2021 Global Burden of Disease Study. Descriptive statistics were mainly conducted using disability-adjusted life years (DALYs) and deaths of HFPG-attributable MASLD from 1990 to 2021, as well as their age-standardized rates (ASRs) and population-attributable fractions. Subgroup analyses were conducted by region, age group, and sex. We found that 213.48 thousand DALYs and 10.02 thousand deaths in MASLD were attributable to HFPG worldwide in 2021, with an increase of 2.96 and 3.32 times compared with 1990, respectively. Over the past 32 years, age-standardized DALY rates (ASDRs) have fluctuated upward, reaching 2.45 per 100,000 people in 2021, with an increase of 81.21%. The ASDRs continued to rise in low, low-middle, and high social demographic index (SDI) regions, fluctuated upward at high levels in middle SDI regions, and were relatively low in high-middle SDI regions. People aged 50-69 accounted for the largest proportion of DALYs, while people over 70 had the largest increase of 3.73 times. Men had higher ASDRs, and the sex difference has been gradually expanding over the past 32 years, peaking at the age of 45-49. In conclusion, the burden of HFPG-attributable MASLD has continued to increase globally, with differences in geographical area, age, and sex distribution. HFPG, as a modifiable risk factor, should be given more importance. The implementation of targeted health intervention strategies is recommended for each country based on trends in the burden of HFPG-attributable MASLD.

Nonalcoholic fatty liver disease (NAFLD) is a disease process that is gaining increasing recognition. The global prevalence of NAFLD is increasing in parallel with growing rates of risk factors for NAFLD such as hypertension, obesity, diabetes, and metabolic syndrome. NAFLD has been referred to as a risk factor for cardiovascular disease (CVD). As CVD is the leading cause of morbidity and mortality worldwide, there are constant efforts to describe and alleviate its risk factors. Although there is conflicting data supporting NAFLD as a causative or associative factor for CVD, NAFLD has been shown to be associated with structural, electrical, and atherosclerotic disease processes of the heart. Shared risk factors and pathophysiologic mechanisms between NAFLD and CVD warrant further explication. Pathologic mechanisms such as endothelial dysfunction, oxidative stress, insulin resistance, genetic underpinnings, and gut microbiota dysregulation have been described in both CVD and NAFLD. The mainstay of treatment for NAFLD is lifestyle intervention including physical exercise and hypocaloric intake in addition to bariatric surgery. Investigations into various therapeutic targets to alleviate hepatic steatosis and fibrosis by way of maintaining the balance between lipid synthesis and breakdown. A major obstacle preventing the success of many pharmacologic approaches has been the effects of these medications on CVD risk. The future of pharmacologic treatment of NAFLD is promising as effective medications with limited CVD harm are being investigated.

The aim of this study was to explore the associations of serum remnant cholesterol (RC) levels with the progression and regression of metabolic dysfunction-associated steatotic liver disease (MASLD) in Chinese adults.

We conducted a cross-sectional study in 13,903 individuals who underwent transient elastography tests (cohort 1) and a longitudinal study in 17,752 individuals who underwent at least two health check-up exams with abdominal ultrasound (cohort 2). Anthropometric and biochemical parameters were collected. Serum RC levels were calculated. Noninvasive fibrosis indices such as FIB-4 were evaluated in cohort 2.

In cohort 1, serum RC levels were positively and independently associated with the severity of hepatic steatosis and liver fibrosis according to logistic regression analysis. In cohort 2, baseline serum RC levels were increased in participants with the incidence of MASLD and decreased in participants with the regression of MASLD during the follow-up period. Baseline serum RC levels were independently associated with an increased risk of development and a decreased likelihood of regression of MASLD: the fully adjusted hazard ratios (HR) were 2.785 (95 % CI 2.332-3.236, P < 0.001) and 2.925 (95 % CI 2.361-3.623, P < 0.001), respectively. In addition, when we used FIB-4 to evaluate liver fibrosis, baseline serum RC levels were positively correlated with the incidence of high-intermediate probability of advanced fibrosis. However, we did not find an association between serum RC levels and the regression of liver fibrosis.

Serum RC levels are independently correlated with the progression and regression of MASLD in Chinese adults, suggesting that RC may participate in the pathophysiological process of MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread global disease with significant health burden. Unhealthy lifestyle, obesity, diabetes mellitus (DM), insulin resistance, and genetics have been implicated in the pathogenesis of MASLD. A significant degree of heterogeneity exists among each of above-mentioned risk factors. Heterogeneity of these risk factors translates into the heterogeneity of MASLD. On the other hand, MASLD can itself lead to insulin resistance and DM. Such heterogeneity makes it difficult to assess the natural course of an individual with MASLD in clinical practice. At present MASLD is considered as one disease despite the variability of etiopathogenic processes, and we lack the consensus definitions of unique subtypes of MASLD. In this review, pathogenic processes of MASLD are discussed and a need of subtyping is recommended.

Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), can promote the development of cirrhosis, hepatocellular carcinoma, cardiovascular disease, and type 2 diabetes. Similarly, type 2 diabetes confers the greatest risk for the development of NASH, especially when associated with obesity. Although lifestyle changes are critical to success, early implementation of pharmacological treatments for obesity and type 2 diabetes are essential to treat NASH and avoid disease progression. This article reviews current guidance regarding the use of pharmacological agents such as pioglitazone, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors in the setting of NAFLD and NASH. It also reviews the latest information on new drugs currently being investigated for the treatment of NASH.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with type 2 diabetes mellitus (T2DM) as a major predictor. Insulin resistance and chronic inflammation are key pathways in the pathogenesis of T2DM leading to NAFLD and vice versa, with the synergistic effect of NAFLD and T2DM increasing morbidity and mortality risks. This meta-analysis aims to quantify the prevalence of NAFLD and the prevalence of clinically significant and advanced fibrosis in people with T2DM.

MEDLINE and Embase databases were searched from inception until 13 February 2023. The primary outcomes were the prevalence of NAFLD, non-alcoholic steatohepatitis (NASH) and fibrosis in people with T2DM. A generalised linear mixed model with Clopper-Pearson intervals was used for the analysis of proportions with sensitivity analysis conducted to explore heterogeneity between studies.

156 studies met the inclusion criteria, and a pooled analysis of 1 832 125 patients determined that the prevalence rates of NAFLD and NASH in T2DM were 65.04% (95% CI 61.79% to 68.15%, I2=99.90%) and 31.55% (95% CI 17.12% to 50.70%, I2=97.70%), respectively. 35.54% (95% CI 19.56% to 55.56%, I2=100.00%) of individuals with T2DM with NAFLD had clinically significant fibrosis (F2-F4), while 14.95% (95% CI 11.03% to 19.95%, I2=99.00%) had advanced fibrosis (F3-F4).

This study determined a high prevalence of NAFLD, NASH and fibrosis in people with T2DM. Increased efforts are required to prevent T2DM to combat the rising burden of NAFLD.

CRD42022360251.

Atherosclerotic dyslipidemia (AD) is associated with an increased risk of cardiovascular diseases and stroke events, but the effect of AD among acute ischemic stroke (AIS) patients undergoing intravenous thrombolysis is unclear. This study aimed to investigate the relationship between AD and long-term stroke recurrence in AIS patients undergoing intravenous thrombolysis.

This prospective cohort study included 499 AIS patients treated with intravenous thrombolysis. Stroke subtype was classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria, patients' clinical characteristics, and results from multiple diagnostic tests. The primary endpoint event was ischemic stroke recurrence; the time to first AIS recurrence was estimated using Kaplan‒Meier analysis and compared using the two-sided Log rank test. Cox univariate and multivariate regression analyses were used to assess the association between AD and long-term stroke recurrence.

Of the 499 patients with AIS treated with rt-PA intravenous thrombolysis, 80 (16.0%) had AD, and 60 (12.0%) had a stroke recurrence event. Kaplan‒Meier analysis showed that the stroke recurrence rate was significantly higher in patients with AD than in those without AD (p = 0.035, log rank test) and in the large-artery disease (LAD) subtype (p = 0.006, log rank test). Multivariate Cox regression analysis showed that AD (HR = 2.363, 95% CI: 1.294-4.314, P = 0.005) and atrial fibrillation (HR = 2.325, 95% CI: 1.007-5.366, P = 0.048) were associated with an increased risk of long-term stroke recurrence in AIS patients who underwent intravenous thrombolysis. Furthermore, AD was associated with an increased risk of stroke recurrence in patients undergoing intravenous thrombolysis in the LAD subtype (HR = 3.122, 95% CI: 1.304-7.437, P = 0.011).

We found that AD increases the risk of long-term stroke recurrence in AIS patients undergoing intravenous thrombolysis. This association may be stronger in the LAD subtype.

Traditional classification systems of metabolic-associated fatty liver disease (MAFLD) do not account for the high rate of extrahepatic complications. To create a new classification of MAFLD using metabolic parameters to identify risks of complications more accurately.

The retrospective study included MAFLD patients from the First Affiliated Hospital of Sun Yat-sen University for model development, and the model was validated respectively using Chinese cohort and UK Biobank database. Cluster analysis with k-means cluster was built using age, body mass index (BMI), glycosylated hemoglobin (HbA1c), total cholesterol/high density lipoprotein cholesterol (HDL-C) ratio, triglyceride, and lipoprotein(a) [Lp(a)] levels. Cox regression models were used to compare the risk of type 2 diabetes (T2DM), chronic heart disease (CHD), stroke and mortality between the clusters.

1038 MAFLD patients from cross-sectional population were recruited for the model derivation, with 10,451 cases (33.4 % of MAFLD) from Chinese cohort and 304,141 cases (34.9 % of MAFLD, 1010 cases with magnetic resonance imaging proton density fat fraction measurement [MRI-PDFF]) from the international cohort validated. Five replicable clusters of MAFLD patients were identified: Cluster 1(mild obesity and dyslipidemia-related), Cluster 2 (age related), Cluster 3 (severe insulin resistance-related), Cluster 4[high Lp(a)-related], and Cluster 5 (severe mixed hyperlipidemia-related). Patients in different clusters exhibited differences in the development of T2DM, CHD, stroke and all-causes mortality. Patients in Cluster 3 had significantly worst survival outcomes and higher risks of T2DM and CVD than those in other clusters.

The novel classification offers improved discrimination of new-onset MAFLD patients with different metabolic complications.

NAFLD is currently considered the most common liver disease worldwide and mounting data support its strong link with atherosclerotic cardiovascular disease (ASCVD). This association is important as cardiovascular disease (CVD) is generally recognized as the leading cause of death in individuals with NAFLD. However, NAFLD represents a heterogeneous condition showing a wide spectrum of clinical and pathophysiological sub-phenotypes with different adverse outcomes ranging from ASCVD to liver damage progression. The contribution to NAFLD pathogenesis of different environmental, metabolic, and genetic factors underlies this heterogeneity. The more frequent phenotype of NAFLD patients is associated with metabolic dysfunctions such as obesity and insulin-resistant syndrome and this has been recently named as Metabolic Associated Fatty Liver disease (MAFLD). However, NAFLD is encountered also in subjects without insulin resistance and metabolic alterations and in whom genetic factors play a major role. It has been suggested that these individuals are at risk of liver disease progression but not of cardiovascular complications. Separating metabolic from genetic factors could be useful in disentangling the intricate relationship between NAFLD and atherosclerosis. In the present review, we aim to address the epidemic of NAFLD, its epidemiologically association with ASCVD complications and the overall mechanisms involved in the pathophysiology of atherosclerotic vascular damage in NAFLD patients. Finally, we will revise the potential role of genetics in identifying disease subtyping and predicting individualised CVD risk.

Liver stiffness is an indirect marker of liver fibrosis, which predicts clinical outcomes in patients with nonalcoholic fatty liver disease (NAFLD). The aim of the present systematic review and meta-analysis is to summarize evidence on the prevalence of elevated liver stiffness in patients with diabetes.

We systematically searched PubMed-MEDLINE and Scopus from inception to May 2022 for observational studies reporting the prevalence of elevated liver stiffness diagnosed by vibration controlled transient elastography (VCTE) in adult patients with either type 1 (T1D) or type 2 diabetes (T2D). Prevalence values from individual studies were meta-analyzed using random effects models. Subgroup and sensitivity analyses were performed to identify potential sources of heterogeneity.

Of the 428 titles initially scrutinized, 29 studies fulfilled the criteria and were included, providing data on 390 patients with T1D and 10,487 patients with T2D. Prevalence rates of elevated liver stiffness were 5.2% (95% CI 1.1-9.2) in patients with T1D and 19.8% (95% CI 16.8-22.8) in patients with T2D. In studies performed in patients with T2D, multivariate meta-regression analysis showed that higher body mass index, higher age, a higher proportion of males, lower VCTE cut-off and Asian ethnicity were associated with increased prevalence rates. This model explained 32.7% of the observed heterogeneity. No signs of publication bias were identified by visual inspection of the funnel plot or by Egger's test.

This meta-analysis indicates that 1 in 20 patients with T1D and 1 in 5 patients with T2D has elevated liver stiffness, indicative of potential significant or advanced liver fibrosis.

To investigate longitudinal changes in the liver stiffness measurement (LSM) in the general adult population without known liver disease and to describe its association with metabolic risk factors, with a special focus on subjects with non-alcoholic fatty liver disease (NAFLD) and dysglycemia.

A longitudinal adult population-based cohort study was conducted in Catalonia. LSM was measured by transient elastography (TE) at baseline and follow-up (median: 4.2 years). Subgroup with NAFLD and dysglycemia were analyzed. Moderate-to-advanced liver fibrosis was defined as LSM ≥8.0 kPa and LSM ≥9.2 kPa respectively.

Among 1.478 subjects evaluated, the cumulative incidence of LSM ≥8.0 kPa and ≥9.2 kPa at follow-up was 2.8% and 1.9%, respectively. This incidence was higher in NAFLD (7.1% for LSM ≥8.0 kPa and 5% for LSM ≥9.2 kPa) and dysglycemia (6.2% for LSM ≥8.0 kPa and 4.7% for LSM ≥9.2 kPa) subgroups. In the global cohort, the multivariate analyses showed that dysglycemia, abdominal obesity and atherogenic dyslipidemia were significantly associated with progression to moderate-to-advanced liver fibrosis. Female sex was negatively associated. In subjects with NAFLD, abdominal obesity and dysglycemia were associated with changes in LSM to ≥8.0 kPa and ≥9.2 kPa at follow-up. A decline in LSM value to <8 kPa was observed in 64% of those subjects with a baseline LSM ≥8.0 kPa.

In this population study, the presence of abdominal obesity and dysglycemia were the main risk metabolic factors associated with moderate-to-advanced liver fibrosis development over time in general populations as well as in subjects with NAFLD.

Sexual dimorphism has been reported in non-alcoholic fatty liver disease (NAFLD), similar to the sex differences evident with cardiovascular disease. Type 2 diabetes mellitus (T2D) significantly increases the risk and severity of NAFLD, but there is scarce information on whether T2D or altered glucose metabolism can modify the prevalence of NAFLD in men and women of reproductive age.

To investigate the relationship between age, sex and NAFLD in subjects with and without dysglycemia.

We analyzed 2,790 patients. NAFLD was characterized using established diagnostic criteria: one or more positive results on the fatty liver index and hepatic ultrasound. Liver fibrosis (liver stiffness measurement [LSM] ≥8.0 kPa) was assessed by Fibroscan^®. For analysis purposes, we included both T2D and prediabetes under the predefined condition of dysglycemia.

The global prevalence of NAFLD was higher in men than in women (50% and 34%; P<0.001), and the prevalence increased with age in both sexes. Older women (≥ 50 years) had a higher prevalence than younger women (<50 years), both in the overall cohort and in non-dysglycemic subjects. In dysglycemic subjects, the prevalence of NAFLD was slightly higher in men (68% vs 61%, p=0.021); in younger subjects, there were no differences in the prevalence of NAFLD between men and women (68% vs 64%, respectively; p=0.635). We found an interaction between dysglycemia and female sex (odds ratio [OR] 1.6 95% confidence interval [CI] 1.0-2.4, p=0.030), and between and age ≥50 years (OR 0.6, 95% CI 0.3-1.0, p=0.046). The global prevalence of LSM ≥8.0 kPa was higher in men compared with women (8% vs 4%; p< 0.001). This prevalence increased with age, mainly in men. We did not find any association between liver fibrosis and age and gender.

While the global prevalence of NAFLD is higher in men than in women across all ages, younger women with dysglycemia have a similar risk of developing NAFLD as men of a similar age. Therefore, the presence of dysglycemia may erase the protective effect of female sex against fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a relatively novel classification which downplays the importance of alcohol in the definition of non-alcoholic fatty liver disease (NAFLD) and emphasizes the metabolic risk factors that underlie progression of NAFLD-associated pathology. All people with type 2 diabetes (T2D) and hepatic fat content >5% by biomarkers, imaging or biopsy are considered to have MAFLD. Since there have been very few published studies of MAFLD in diabetes, the present review assesses contemporary methods for quantifying liver fat and fibrosis (including those based on magnetic resonance imaging) with special reference to T2D, their prognostic implications for people with T2D and MAFLD, and the factors and interventions that modify disease progression and outcomes. The changing epidemiology of obesity and cardiovascular disease and new therapies for MAFLD on the horizon with potential implications for T2D are discussed.