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ETHNOPHARMACOLOGICAL RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver-related morbidity and mortality, with hepatic steatosis being the hallmark symptom. Salvia miltiorrhiza Bunge (Smil, Dan-Shen) and Ligusticum striatum DC (Lstr, Chuan-Xiong) are commonly used to treat cardiovascular diseases and have the potential to regulate lipid metabolism. However, whether Smil/Lstr combo can be used to treat NAFLD and the mechanisms underlying its lipid-regulating properties remain unclear. PURPOSE: To assess the feasibility and reliability of a short-term high-fat diet (HFD) induced zebrafish model for evaluating hepatic steatosis phenotype and to investigate the liver lipid-lowering effects of Smil/Lstr, as well as its active components. METHODS: The phenotypic alterations of liver and multiple other organ systems were examined in the HFD zebrafish model using fluorescence imaging and histochemistry. The liver-specific lipid-lowering effects of Smil/Lstr combo were evaluated endogenously. The active molecules and functional mechanisms were further explored in zebrafish, human hepatocytes, and hamster models. RESULTS: In 5-day HFD zebrafish, significant lipid accumulation was detected in the blood vessels and the liver, as evidenced by increased staining with Oil Red O and fluorescent lipid probes. Hepatic hypertrophy was observed in the model, along with macrovesicular steatosis. Smil/Lstr combo administration effectively restored the lipid profile and alleviated hepatic hypertrophy in the HFD zebrafish. In oleic-acid stimulated hepatocytes, Smil/Lstr combo markedly reduced lipid accumulation and cell damage. Subsequently, based on zebrafish phenotypic screening, the natural phthalide senkyunolide I (SEI) was identified as a major molecule mediating the lipid-lowering activities of Smil/Lstr combo in the liver. Moreover, SEI upregulated the expression of the lipid metabolism regulator PPARα and downregulated fatty acid translocase CD36, while a PPARα antagonist sufficiently blocked the regulatory effect of SEI on hepatic steatosis. Finally, the roles of SEI on hepatic lipid accumulation and PPARα signaling were further verified in the hamster model. CONCLUSIONS: We proposed a zebrafish-based screening strategy for modulators of hepatic steatosis and discovered the regulatory roles of Smil/Lstr combo and its component SEI on liver lipid accumulation and PPARα signaling, suggesting their potential value as novel candidates for NAFLD treatment.
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Modelos Animales de Enfermedad , PPAR alfa , Transducción de Señal , Pez Cebra , Animales , Transducción de Señal/efectos de los fármacos , PPAR alfa/metabolismo , Humanos , Masculino , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Dieta Alta en Grasa , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Cricetinae , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Mesocricetus , Células Hep G2 , Benzofuranos/farmacología , Hígado Graso/tratamiento farmacológicoRESUMEN
The natural history of metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD), is complex and long. A minority of patients develop inflammation and risk progressive fibrosis that can result in cirrhosis. Progression to cirrhosis occurs in 3-5% of patients and often takes more than 20 years. This narrative review presents an update on the natural history of MASLD, discussing studies and risk estimates for progression to severe outcomes, such as decompensated cirrhosis or hepatocellular carcinoma. We highlight the dynamic progression of liver damage, how to identify patients whose disease progresses over time, and how risk factors might be mitigated to reduce the risk for disease progression.
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Progresión de la Enfermedad , Cirrosis Hepática , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/patología , Factores de Riesgo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/complicaciones , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologíaRESUMEN
BACKGROUND: Frailty is associated with obesity-related comorbidities, but the relationship with nonalcoholic fatty liver disease (NAFLD) in people with HIV has been incompletely described. Our objective was to assess the associations between NAFLD and frailty. METHODS: Cross-sectional and longitudinal analysis of men in the Multicenter AIDS Cohort Study. NAFLD was defined as a liver/spleen ratio <1.0 on abdominal computed tomography scans; frailty was defined by the frailty phenotype as having 3 of the following: weakness, slowness, weight loss, exhaustion, and low physical activity. RESULTS: Men without (n = 200) and with HIV (n = 292) were included. NAFLD prevalence was 21% vs 16% and frailty 12% vs 17%, respectively. Among men with NAFLD, frailty was more prevalent in men without HIV (21% vs 11%). In multivariate analysis, NAFLD was significantly associated with frailty after controlling for significant variables. Men without HIV and NAFLD had 2.6 times higher probability [95% confidence interval (CI): 1.2- to 5.7] of frailty relative to men with neither HIV nor NAFLD. This association was not seen in men with HIV. The probability of frailty was higher among men without HIV with NAFLD (27% vs 10% in men without NAFLD) but lower among men with HIV with NAFLD (14% vs 19% in men without NAFLD). No significant relationships were found in longitudinal analyses. CONCLUSIONS: NAFLD was independently associated with frailty among men without HIV but not men with HIV, despite increased prevalence of frailty among men with HIV. The mechanisms of the muscle-liver-adipose tissue axis underlying NAFLD might differ by HIV serostatus.
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Fragilidad , Infecciones por VIH , Enfermedad del Hígado Graso no Alcohólico , Humanos , Masculino , Fragilidad/epidemiología , Persona de Mediana Edad , Estudios Transversales , Infecciones por VIH/complicaciones , Adulto , Estudios Longitudinales , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Prevalencia , Seropositividad para VIH/complicacionesRESUMEN
Background US shear-wave elastography (SWE) and vibration-controlled transient elastography (VCTE) enable assessment of liver stiffness, an indicator of fibrosis severity. However, limited reproducibility data restrict their use in clinical trials. Purpose To estimate SWE and VCTE measurement variability in nonalcoholic fatty liver disease (NAFLD) within and across systems to support clinical trial diagnostic enrichment and clinical interpretation of longitudinal liver stiffness. Materials and Methods This prospective, observational, cross-sectional study (March 2021 to November 2021) enrolled adults with NAFLD, stratified according to the Fibrosis-4 (FIB-4) index (≤1.3, >1.3 and <2.67, ≥2.67), at two sites to assess SWE with five US systems and VCTE with one system. Each participant underwent 12 elastography examinations over two separate days within 1 week, with each day's examinations conducted by a different operator. VCTE and SWE measurements were reported in units of meters per second. The primary end point was the different-day, different-operator reproducibility coefficient (RDCDDDO) pooled across systems for SWE and individually for VCTE. Secondary end points included system-specific RDCDDDO, same-day, same-operator repeatability coefficient (RCSDSO), and between-system same-day, same-operator reproducibility coefficient. The planned sample provided 80% power to detect a pooled RDCDDDO of less than 35%, the prespecified performance threshold. Results A total of 40 participants (mean age, 60 years ± 10 [SD]; 24 women) with low (n = 17), intermediate (n = 15), and high (n = 8) FIB-4 scores were enrolled. RDCDDDO was 30.7% (95% upper bound, 34.4%) for SWE and 35.6% (95% upper bound, 43.9%) for VCTE. SWE system-specific RDCDDDO varied from 24.2% to 34.3%. The RCSDSO was 21.0% for SWE (range, 13.9%-35.0%) and 19.6% for VCTE. The SWE between-system same-day, same-operator reproducibility coefficient was 52.7%. Conclusion SWE met the prespecified threshold, RDCDDDO less than 35%, with VCTE having a higher RDCDDDO. SWE variability was higher between different systems. These estimates advance liver US-based noninvasive test qualification by (a) defining expected variability, (b) establishing that serial examination variability is lower when performed with the same system, and (c) informing clinical trial design. ClinicalTrials.gov Identifier NCT04828551 © RSNA, 2024 Supplemental material is available for this article.
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Diagnóstico por Imagen de Elasticidad , Enfermedad del Hígado Graso no Alcohólico , Humanos , Diagnóstico por Imagen de Elasticidad/métodos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Femenino , Masculino , Reproducibilidad de los Resultados , Persona de Mediana Edad , Estudios Prospectivos , Estudios Transversales , Adulto , Hígado/diagnóstico por imagen , Anciano , Cirrosis Hepática/diagnóstico por imagenRESUMEN
BACKGROUND AND AIMS: Epidemiological evidence on the associations between female reproductive features and nonalcoholic fatty liver disease (NAFLD) is conflicting. To explore their causalities, we conducted a Mendelian randomization (MR) study. METHODS: Summary-level data were obtained, and univariable MR was performed to explore the causalities between female reproductive features and NAFLD. And we performed multivariable MR and MR mediation analysis to explore the mediation effects of educational attainment (EA) and body mass index (BMI) for these associations. Sensitivity analyses were performed to evaluate pleiotropy and heterogeneity. RESULTS: There were causal effects of age at menarche (AAMA) (odds ratio [OR]: 0.817, 95% confidence interval [CI]: 0.736-0.907, per year-increase), age at first birth (AFB) (OR: 0.851, 95%CI: 0.791-0.926, per year-increase) and age at first sexual intercourse (AFS) (OR: 0.676, 95%CI: 0.511-0.896, per standard deviation-increase) on NAFLD risk. Besides, the causal effects were also observed on NAFLD phenotypes including liver fat content (LFC) and alanine aminotransferase (ALT). Further mediation analysis showed that BMI mediated partial proportion of effects of AAMA and AFS on NAFLD/ALT, AFB on NAFLD/LFC/ALT, while EA mediated partial proportion of effects of AFB on NAFLD/LFC/ALT, and AFS on NAFLD/ALT. CONCLUSIONS: This study provided convincing evidence that early AAMA, AFB, and AFS were risk factors for NAFLD. Reproductive health education, obesity management, and education spread might be the beneficial strategies for NAFLD prevention.
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Índice de Masa Corporal , Análisis de la Aleatorización Mendeliana , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/etiología , Femenino , Factores de Riesgo , Menarquia , Reproducción/genética , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad , Oportunidad RelativaRESUMEN
Numerous studies highlight the potential of natural antioxidants, such as those found in foods and plants, to prevent or treat nonalcoholic fatty liver disease (NAFLD). Inflammation is a key factor in the progression from high-fat diet-induced NAFLD to nonalcoholic steatohepatitis (NASH). Injured liver cells and immune cells release inflammatory cytokines, activating hepatic stellate cells. These cells acquire a profibrogenic phenotype, leading to extracellular matrix accumulation and fibrosis. Persistent fibrosis can progress to cirrhosis. Fatty infiltration, oxidative stress, and inflammation exacerbate fatty liver diseases. Thus, many plant-derived antioxidants, like silymarin, silibinin, curcumin, resveratrol, berberine, and quercetin, have been extensively studied in experimental models and clinical patients with NAFLD. Experimentally, these compounds have shown beneficial effects in reducing lipid accumulation, oxidative stress, and inflammatory markers by modulating the ERK, NF-κB, AMPKα, and PPARγ pathways. They also help decrease metabolic endotoxemia, intestinal permeability, and gut inflammation. Clinically, silymarin and silibinin have been found to reduce transaminase levels, while resveratrol and curcumin help alleviate inflammation in NAFLD patients. However, these phytocompounds exhibit poor water solubility, leading to low oral bioavailability and hindering their biological efficacy. Additionally, inconclusive clinical results highlight the need for further trials with larger populations, longer durations, and standardized protocols.
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Suplementos Dietéticos , Inflamación , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , AnimalesRESUMEN
Non-alcoholic fatty liver disease (NAFLD) and myocardial infarction (MI) are two major health burdens with significant prevalence and mortality. This study aimed to explore the co-expressed genes to understand the relationship between NAFLD and MI and identify potential crucial biomarkers of NAFLD-related MI using bioinformatics and machine learning. Functional enrichment analysis was conducted, a co-protein-protein interaction (PPI) network diagram was constructed, and support vector machine-recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) techniques were employed to identify one differentially expressed gene (DEG), Thrombospondin 1 (THBS1). THBS1 demonstrated strong performance in distinguishing NAFLD patients (AUC = 0.981) and MI patients (AUC = 0.900). Immuno-infiltration analysis revealed significantly lower CD8+ T cells and higher neutrophil levels in patients with NAFLD and MI. CD8+ T cells and neutrophils were effective in distinguishing NAFLD/MI from healthy controls. Correlation analysis showed that THBS1 was positively correlated with CCR (chemokine receptor), MHC class (major histocompatibility complex class), neutrophils, parainflammation, and Tfh (follicular helper T cells), and negatively correlated with CD8+ T cells, cytolytic activity, and TIL (tumor-infiltrating lymphocytes) in NAFLD and MI patients. THBS1 emerged as a novel biomarker for diagnosing NAFLD/MI in comparison to healthy controls. The results indicate that CD8+ T cells and neutrophils could serve as inflammatory immune features for differentiating patients with NAFLD/MI from healthy individuals.
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Enfermedad del Hígado Graso no Alcohólico , Trombospondina 1 , Humanos , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Trombospondina 1/genética , Trombospondina 1/metabolismo , Infarto del Miocardio/inmunología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/genética , Máquina de Vectores de Soporte , Biomarcadores/metabolismo , Biomarcadores/análisisRESUMEN
BACKGROUND AND AIM: Metabolic dysfunction-associated steatotic liver disease (MASLD) formerly known as non-alcoholic fatty liver disease (NAFLD) is the most common liver condition globally. The FIB-4 test is used to detect fibrosis in fatty liver disease but has limited accuracy in predicting liver stiffness, resulting in high rates of false positives and negatives. The new BAST scoring system, incorporating waist circumference, AST, and BMI, has been developed to assess the presence of fibrosis in NAFLD patients. This study compares the effectiveness of BAST and FIB-4 in predicting liver fibrosis in MASLD patients. PATIENTS AND METHODS: The study included 140 non-diabetic MASLD patients who underwent transient elastography measurement. BAST score and FIB-4 were calculated for each patient. Patients were grouped based on fibrosis severity; F1, F2, and F3-F4. The sensitivity and specificity of the BAST score and FIB-4 were assessed using receiver operating characteristic curves. RESULTS: The BAST score increased significantly with fibrosis progression from F1 to F3-F4. In differentiating advanced fibrosis (F2-F3) from mild/moderate fibrosis (F1-F2), the BAST score at cutoff ≤ - 0.451 showed better diagnostic performance with 90.70% sensitivity, 74.07% specificity, 84.8% PPV and 83.3% NPV compared to FIB-4 that had 60.47% sensitivity, 50.0% specificity, 65.8% PPV and 44.3% NPV. Similarly, for differentiating between F1 and F2 fibrosis, the BAST score at cutoff ≤ - 1.11 outperformed FIB-4, with 80.23% sensitivity, 79.49% specificity, 89.6% PPV and 64.6% NPV, while FIB-4 had 59.30% sensitivity, 51.28% specificity, 72.9% PPV and 36% NPV. CONCLUSIONS: The BAST score is a better predictor of liver fibrosis in MASLD compared to FIB-4, especially in cases of advanced fibrosis or cirrhosis.
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Diagnóstico por Imagen de Elasticidad , Cirrosis Hepática , Enfermedad del Hígado Graso no Alcohólico , Humanos , Masculino , Femenino , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/complicaciones , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/patología , Diagnóstico por Imagen de Elasticidad/métodos , Adulto , Índice de Severidad de la Enfermedad , Curva ROC , AncianoRESUMEN
Abnormal SUMOylation is implicated in non-alcoholic fatty liver disease (NAFLD) progression. Forkhead box protein A1 (FoxA1) has been shown to protect liver from steatosis, which was down-regulated in NAFLD. This study elucidated the role of FoxA1 deSUMOylation in NAFLD. NAFLD models were established in high-fat diet (HFD)-induced mice and palmitate acid (PAL)-treated hepatocytes. Hepatic steatosis was evaluated by biochemical and histological methods. Lipid droplet formation was determined by BODIPY and Oil red O staining. Target molecule levels were analyzed by RT-qPCR, Western blotting, and immunohistochemistry staining. SUMOylation of FoxA1 was determined by Ni-NTA pull-down assay and SUMOylation assay Ultra Kit. Protein interaction and ubiquitination were detected by Co-IP. Gene transcription was assessed by ChIP and dual luciferase reporter assays. Liver FoxA1 knockout mice developed severe liver steatosis, which could be ameliorated by sirtuin 6 (Sirt6) overexpression. Nutritional stresses reduced Sumo2/3-mediated FoxA1 SUMOylation at lysine residue K6, which promoted lipid droplet formation by repressing fatty acid ß-oxidation. Moreover, Sirt6 was a target gene of FoxA1, and Sirt6 transcription activity was restrained by deSUMOylation of FoxA1 at site K6. Furthermore, nutritional stresses-induced deSUMOylation of FoxA1 promoted the ubiquitination and degradation of FoxA1 with assistance of murine double minute 2 (Mdm2). Finally, activating FoxA1 SUMOylation delayed the progression of NAFLD in mice. DeSUMOylation of FoxA1 at K6 promotes FoxA1 degradation and then inhibits Sirt6 transcription, thereby suppressing fatty acid ß-oxidation and facilitating NAFLD development. Our findings suggest that FoxA1 SUMOylation activation might be a promising therapeutic strategy for NAFLD.
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Regulación hacia Abajo , Factor Nuclear 3-alfa del Hepatocito , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico , Sirtuinas , Sumoilación , Animales , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Factor Nuclear 3-alfa del Hepatocito/genética , Ratones , Humanos , Sirtuinas/metabolismo , Sirtuinas/genética , Masculino , Ratones Endogámicos C57BL , Dieta Alta en Grasa , Modelos Animales de EnfermedadRESUMEN
Objective: To determine the prevalence of non-alcoholic fatty liver disease, and the effect of oral hypoglycaemic drugs and lifestyle modifications in reducing fatty liver changes and liver enzymes in these patients. METHODS: The comparative, observational study was conducted at the Department of Pharmacology, Sohail University, Karachi, from October 2022 to October 2023, and comprised patients of either gender having elevated liver enzymes and ultrasound finding of fatty liver changes along with raised glycated haemoglobin, transaminases, total cholesterol and triglycerides. The participants were prescribed oral hypoglycaemic agents by endocrinologists. Those given empaglifazolin + metformin were in group A, empaglifazolin + linglaptin in group B, sitaglaptin + metformin in group C, metformin alone in group D and sitaglaptin alone in group E. Lifestyle modifications were advised in all the treatment groups, while control group F was only advised lifestyle modifications. The intervention lasted 3 months. Investigations included B-mode ultrasound liver, liver enzymes and glycated haemoglobin, which were done at baseline and after the intervention. Data was analysed using SPSS 25. RESULTS: Of 200 patients, 40 were males and 160 were females in ratio of 1:4. The overall mean age was 48±16 years. There were 154(77%) patients who had non-alcoholic fatty liver disease with type 2 diabetes mellitus, while 46(23%) had only fatty liver changes. There were 50(25%) patients in group A, 30(15%) in group B, 30(15%) in group C, 40(20%) in group D, 10(5%) in group E and 40(20%) in group F. Post-intervention improvement was noted in 48(24%) patients, with 20(41.7%) of them being in group A. Conclusion: The prevalence of non-alcoholic fatty liver disease with type 2 diabetes was high. Combination of empagliflozin + metformin along with lifestyle modifications was highly effective in reducing fatty changes and the level of liver enzymes.
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Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Masculino , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Persona de Mediana Edad , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/administración & dosificación , Adulto , Metformina/uso terapéutico , Metformina/administración & dosificación , Hemoglobina Glucada/metabolismo , Ultrasonografía , Hígado/diagnóstico por imagen , Hígado/efectos de los fármacos , Administración Oral , Pakistán/epidemiologíaRESUMEN
Background: Nonalcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder strongly linked to type 2 diabetes mellitus (T2DM). Understanding the predictive value of lipid parameters in identifying abnormal glucose metabolism in NAFLD patients is crucial for early intervention. Methods: This study analyzed data from the National Health and Nutrition Examination Survey(NHANES) database (2017-2020) involving 1066 NAFLD patients. Participants were categorized into three groups: T2DM (n=414), prediabetes mellitus (pre-DM) (n=507), and normoglycemia (NG) (n=145). Traditional lipid parameters [triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C)] and nontraditional lipid parameters [atherogenic index of plasma (AIP), residual cholesterol (RC), and non-high-density lipoprotein cholesterol (non-HDL-C)] were evaluated for their association with T2DM and pre-DM. Results: Elevated TG levels were significantly associated with an increased risk of T2DM and pre-DM, whereas high HDL-C demonstrated a protective effect. Among nontraditional lipid parameters, increased AIP and RC were most strongly associated with T2DM risk, while high non-HDL-C was best associated with the development of pre-DM. Stratified analyses revealed that these associations were stronger in younger, non-obese, smoking, and female NAFLD patients. Conclusion: Nontraditional lipid parameters, particularly AIP and RC, show superior predictive value over traditional lipid parameters in identifying abnormal glucose metabolism in NAFLD patients. Incorporating these novel biomarkers into clinical practice could enhance early detection and prevention strategies for T2DM and pre-DM in this high-risk population.
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Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Encuestas Nutricionales , Estado Prediabético , Humanos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Femenino , Masculino , Estado Prediabético/sangre , Estado Prediabético/epidemiología , Estado Prediabético/metabolismo , Persona de Mediana Edad , Adulto , Factores de Riesgo , Lípidos/sangre , Biomarcadores/sangre , Anciano , Estudios Transversales , Glucemia/metabolismo , Glucemia/análisisRESUMEN
Background: Observational data posits a correlation between reproductive traits and nonalcoholic fatty liver disease (NAFLD), but their causal inference is still unclear. This investigation seeks to elucidate the causal influence of reproductive traits on NAFLD and determine the intervening role of health condition and socioeconomic status in these connections. Methods: Utilizing a Mendelian Randomization (MR) approach, this research leveraged a comprehensive dataset from the Genome-wide Association Study (GWAS) database. The study incorporated body mass index, major depression, educational level, household income and Townsend deprivation index as intermediary variables. Initially, a bidirectional two-sample MR study was conducted to explore the genetic associations between reproductive traits and NAFLD. Then, two-step MR analyses were implemented to quantify the extent of mediation by these indicators. The weighted inverse variance method was the primary analytical approach, complemented by several sensitivity analyses to affirm the robustness of the MR assumptions. Finally, these findings were validated in the FinnGen research. Results: The bidirectional MR analysis indicated that earlier reproductive traits (age at menarche, age at first sexual intercourse, and age at first birth) were associated with an elevated risk of NAFLD, absent any evidence of the reverse relationship. Body mass index accounted for 35.64% of the association between premature menarche and NAFLD. Additionally, body mass index, major depression, educational level and household income mediated 41.65%, 14.35%, 37.88%, and 18.59% of the connection between early sexual intercourse and NAFLD, respectively. Similarly, these same variables elucidated 36.36%, 15.58%, 41.56%, and 22.73% of the correlation between younger age at first birth and NAFLD. Conclusion: Our study elucidated the causal relationships between reproductive traits and NAFLD. Potential underlying mechanisms may involve factors such as body mass index, major depression, educational attainment and household income.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Enfermedad del Hígado Graso no Alcohólico , Clase Social , Humanos , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/genética , Femenino , Índice de Masa Corporal , Estado de Salud , Masculino , Adulto , Reproducción/genética , Polimorfismo de Nucleótido Simple , Persona de Mediana Edad , Menarquia/genética , Factores de RiesgoRESUMEN
BACKGROUND: Increasing evidences suggest that nonalcoholic fatty liver disease (NAFLD) is associated with neuropsychiatric disorders. Nevertheless, whether there were causal associations between them remained vague. A causal association between neuropsychiatric disorders and NAFLD was investigated in this study. METHODS: We assessed the published genome-wide association study summary statistics for NAFLD, seven mental disorder-related diseases and six central nervous system dysfunction-related diseases. The causal relationships were first assessed using two-sample and multivariable Mendelian randomization (MR). Then, sensitivity analyses were performed, followed by a reverse MR analysis to determine whether reverse causality is possible. Finally, we performed replication analyses and combined the findings from the above studies. RESULTS: Our meta-analysis results showed NAFLD significantly increased the risk of anxiety disorders (OR = 1.016, 95% CI = 1.010-1.021, P value < 0.0001). In addition, major depressive disorder was the potential risk factor for NAFLD (OR = 1.233, 95% CI = 1.063-1.430, P value = 0.006). Multivariable MR analysis showed that the causal effect of major depressive disorder on NAFLD remained significant after considering body mass index, but the association disappeared after adjusting for the effect of waist circumference. Furthermore, other neuropsychiatric disorders and NAFLD were not found to be causally related. CONCLUSIONS: These results implied causal relationships of NAFLD with anxiety disorders and Major Depressive Disorder. This study highlighted the need to recognize and understand the connection between neuropsychiatric disorders and NAFLD to prevent the development of related diseases.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Trastornos Mentales , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Trastornos Mentales/genética , Trastornos Mentales/epidemiología , Factores de Riesgo , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/epidemiología , Causalidad , Trastornos de Ansiedad/epidemiología , Trastornos de Ansiedad/genéticaRESUMEN
Background: The TyG index, or triglyceride-glucose index, is primarily used as a marker to assess insulin resistance and metabolic health. It increases mortality risk in patients with NAFLD, atherosclerosis, ischemic stroke, or heart failure. However, its association with Carotid Atherosclerosis (CAS) risk in NAFLD patients remains uncertain. Methods: This retrospective cohort study enrolled 739 individuals who participated comprehensive health evaluations at a large public hospital in Yangzhou, China, between January 2021 and December 2023. Among them, 436 were men and 303 were women, and their mean (SD) age was 51.53 ± 11.46 years. The individuals were categorized into three tertiles (Q1, Q2, and Q3), according to the baseline TyG index. Our investigation focused on exploring the correlativity between the TyG and the occurrence of CAS utilizing Cox regression and RCS analyses. Results: During a 3-year follow-up period, 199 patients developed CAS (cumulative incidence rate: 26.93%). A statistical model, adjusted for age, gender, BMI, and other confounders indicated that the HR (95%CI) values for CAS risk in the Q2 and Q3 groups were 3.11(1.87-5.17) and 4.51(2.69-7.56), respectively, with P-values <0.001 for both groups. A sensitivity analysis confirmed these results. Kaplan-Meier survival analysis revealed that CAS risk varied across the groups (P non-linear < 0.05). Conclusion: In individuals diagnosed as NAFLD, the possibility for CAS escalates with the elevation of the TyG value. Therefore, the TyG index is an effective marker for assessing the risk of CAS within this demographic. Large-sample prospective studies are needed to confirm this conclusion in the future.
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Glucemia , Enfermedades de las Arterias Carótidas , Enfermedad del Hígado Graso no Alcohólico , Triglicéridos , Humanos , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/epidemiología , Triglicéridos/sangre , Adulto , Factores de Riesgo , Glucemia/análisis , Glucemia/metabolismo , China/epidemiología , Resistencia a la Insulina , Estudios de Seguimiento , Incidencia , Estudios de Cohortes , Biomarcadores/sangreRESUMEN
Recently, the study of endoplasmic reticulum stress (ERS) and liver disease has attracted much attention, but bibliometric analysis on this field is scarce. Therefore, to address this gap, we conducted a bibliometric analysis to explore the research status, hotspots, and trends in this field. We searched the Web of Science Core Collection database for publications on ERS and liver disease from 2007 to 2022. Bibliometric online analysis platform, VOSviewer, and CiteSpace were used to perform bibliometric analysis. Two thousand seven hundred fifty-one publications were retrieved form the Web of Science Core Collection database. The USA was the most productive and influential country. Seoul National University, International Journal of Molecular Sciences, and Kaufman RJ were the most productive institution, journal, and author. "Endoplasmic reticulum stress," "nonalcoholic fatty liver disease," "inflammation," "oxidative stress" and "insulin resistance" were the high-frequency keywords, "necrosis factor alpha" was the keywords with the strongest citation bursts, and "nonalcoholic fatty liver," "fibrosis" and "lipid droplet" were the keywords that were still bursting in 2022. The number of publications on ERS and liver disease has increased over the past years. The USA was the most productive and influential country. China has become the country with the largest number of annual publications, but it still needs to work on the quality. ERS and nonalcoholic fatty liver disease, especially the insulin resistance and lipotoxicity in hepatocytes may be the research hotspots and trends in this field of ERS and liver disease.
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Bibliometría , Estrés del Retículo Endoplásmico , Hepatopatías , Humanos , Investigación Biomédica/estadística & datos numéricos , Enfermedad del Hígado Graso no Alcohólico , Estrés OxidativoRESUMEN
BACKGROUND: Nonalcoholic steatohepatitis (NASH) is an important etiology of hepatocellular carcinoma (HCC), and there is no established therapy for this syndrome. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor (ROHHAD(NET)) is an extremely rare syndrome considered to be life-threatening, with death occurring around 10 years of age. We present the oldest known autopsy case of this syndrome that developed HCC. This case provided important information on not only improving the course of this syndrome, but also understanding the natural history and therapeutic modalities of NASH and HCC. METHODS: The patient was diagnosed with ROHHAD(NET) syndrome in childhood, and liver cirrhosis due to NASH was diagnosed at age 17. HCC was detected at age 20, and embolization and irradiation were performed. At age 21, she died from accidental acute pancreatitis and subsequent liver failure and pulmonary hemorrhage. RESULTS: Rapid onset of obesity, hypoventilation, and hypothalamic disturbance appeared in childhood and was diagnosed as this syndrome. At age 17, liver cirrhosis due to NASH was diagnosed by liver biopsy, and at age 20, HCC was diagnosed by imaging. Transarterial chemoembolization and irradiation were performed, and the HCC was well controlled for a year. CONCLUSION: At age 21, she died from accidental acute pancreatitis, subsequent liver failure and pulmonary hemorrhage. Autopsy revealed that the HCC was mostly necrotized. This case was valuable not only for other ROHHAD(NET) syndrome cases, but also in improving our understanding of the natural history of NASH and HCC.
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Autopsia , Carcinoma Hepatocelular , Enfermedades Hipotalámicas , Hipoventilación , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Femenino , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/terapia , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/terapia , Hipoventilación/etiología , Hipoventilación/complicaciones , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedades Hipotalámicas/complicaciones , Enfermedades Hipotalámicas/diagnóstico , Obesidad/complicaciones , Tumores Neuroendocrinos/complicaciones , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/terapia , Resultado Fatal , Adulto Joven , Enfermedades del Sistema Nervioso Autónomo/etiología , SíndromeRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent condition in the general population. Although recent studies have demonstrated a link between NAFLD and lipoprotein(a), a low-density lipoprotein-like particle synthesized in the liver, its precise physiological role and mechanism of action remain unclear. This study aimed to investigate the relationship between lipoprotein(a) levels and development of NAFLD and hepatic fibrosis in Korean adults. A total of 1501 subjects who underwent abdominal ultrasonography at least twice as part of a health checkup program were enrolled. Biochemical and ultrasonography results were analyzed longitudinally, and the degree of hepatic fibrosis was calculated in subjects with NAFLD using serum biomarkers, such as fibrosis-4 (FIB-4). During the 3.36-year follow-up period, 352 patients (23.5%) were diagnosed with NAFLD. The subjects were categorized into 4 groups based on their lipoprotein(a) levels. Remarkably, the incidence of NAFLD decreased as the lipoprotein(a) levels increased. Following logistic regression analysis and adjustment for various risk factors, the odds ratio for the development of NAFLD was 0.625 (95% CI 0.440-0.888; Pâ =â .032) when comparing the highest to the lowest tertile of lipoprotein(a). However, no significant association was observed between the occurrence of hepatic fibrosis and lipoprotein(a) levels in subjects with NAFLD. Lipoprotein(a) levels have been identified as a significant predictor of NAFLD development. Additional large-scale studies with extended follow-up periods are required to better understand the effect of lipoprotein(a) on NAFLD and hepatic fibrosis.
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Biomarcadores , Lipoproteína(a) , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Masculino , Femenino , República de Corea/epidemiología , Lipoproteína(a)/sangre , Persona de Mediana Edad , Estudios Longitudinales , Estudios Retrospectivos , Adulto , Biomarcadores/sangre , Factores de Riesgo , Cirrosis Hepática/sangre , Cirrosis Hepática/epidemiología , Ultrasonografía , IncidenciaRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disorder marked by the buildup of triacylglycerols (TGs) in the liver. It includes a range of conditions, from simple steatosis to more severe forms like non-alcoholic steatohepatitis (NASH), which can advance to fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD's prevalence is rising globally, estimated between 10% and 50%. The disease is linked to comorbidities such as obesity, type 2 diabetes, insulin resistance, and cardiovascular diseases and currently lacks effective treatment options. Therefore, researchers are focusing on evaluating the impact of adjunctive herbal therapies in individuals with NAFLD. One herbal therapy showing positive results in animal models and clinical studies is fruits from the Vaccinium spp. genus. This review presents an overview of the association between consuming fruits, juices, and extracts from Vaccinium spp. and NAFLD. The search used the following keywords: ((Vaccinium OR blueberry OR bilberry OR cranberry) AND ("non-alcoholic fatty liver disease" OR "non-alcoholic steatohepatitis")). Exclusion criteria included reviews, research notes, book chapters, case studies, and grants. The review included 20 studies: 2 clinical trials and 18 studies on animals and cell lines. The findings indicate that juices and extracts from Vaccinium fruits and leaves have significant potential in addressing NAFLD by improving lipid and glucose metabolism and boosting antioxidant and anti-inflammatory responses. In conclusion, blueberries appear to have the potential to alleviate NAFLD, but more clinical trials are needed to confirm these benefits.
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Frutas , Enfermedad del Hígado Graso no Alcohólico , Extractos Vegetales , Vaccinium , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/terapia , Humanos , Frutas/química , Vaccinium/química , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Fitoterapia , Jugos de Frutas y VegetalesRESUMEN
NAFLD has emerged as a significant public health concern, with its prevalence increasing globally. Emphasizing the complex relationship between dietary patterns and epigenetic modifications such as DNA methylation or miRNA expression can exert a positive impact on preventing and managing metabolic disorders, including NAFLD, within the 2030 Sustainable Development Goals. This review aims to evaluate the influence of dietary patterns on hepatic epigenetic gene modulation and provide dietary recommendations for the prevention and management of NAFLD in the general population. METHODS: Comprehensive screening and eligibility criteria identified eleven articles focusing on epigenetic changes in NAFLD patients through dietary modifications or nutrient supplementation. RESULTS AND DISCUSSION: Data were organized based on study types, categorizing them into evaluations of epigenetic changes in NAFLD patients through dietary pattern modifications or specific nutrient intake. CONCLUSIONS: The study highlights the importance of dietary interventions in managing and preventing NAFLD, emphasizing the potential of dietary patterns to influence hepatic epigenetic gene modulation. This study provides valuable insights and recommendations to mitigate the risk of developing NAFLD: (i) eat a primarily plant-based diet; (ii) increase consumption of high-fiber foods; (iii) consume more polyunsaturated and monounsaturated fatty acids; (iv) limit processed foods, soft drinks, added sugars, and salt; and (v) avoid alcohol.