Severity Of Nonalcoholic Fatty Liver Disease Research Articles

Hepatocyte-derived DPP4 regulates portal GLP-1 bioactivity, glucose production, and its absence alters liver disease progression.

Elevated circulating dipeptidyl-peptidase 4 is a biomarker for liver disease, but its involvement in gluconeogenesis and in metabolic-associated fatty liver disease (MAFLD) progression remains unclear. Here we identified that DPP4 in hepatocytes but not Tie2+ endothelial cells regulates the local bioactivity of incretin hormones and gluconeogenesis. However, the complete absence of DPP4 (Dpp4-/-) in aged mice with metabolic syndrome accelerates liver fibrosis without altering dyslipidemia and steatosis. Analysis of transcripts from the livers of whole body Dpp4-/- displayed enrichment for inflammasome, p53, and senescence programs compared to littermate controls. High-fat high-cholesterol (HFHC)-feeding decreased Dpp4 expression in F4/80+ cells, with only minor changes in immune signaling. Moreover, in a lean mouse model of severe non-alcoholic fatty liver disease (NAFLD), phosphatidylethanolamine N-methyltransferase (Pemt -/-) mice fed with HFHC diet, we observed a 4-fold increase in circulating DPP4, disassociating its release from obesity. Lastly, we evaluated DPP4 levels in patients with hepatitis C infection with dysglycemia (HOMA-IR > 2) who underwent direct antiviral treatment (with or without ribavirin). DPP4 protein levels decreased with viral clearance, and DPP4 activity levels were reduced at longer-term follow-up in ribavirin-treated patients, although metabolic factors did not improve. These data suggest elevations in DPP4 during HCV infection are not primarily regulated by metabolic disturbances.

The Association between Non-Alcoholic Fatty Liver Disease and Dynapenia in Men Diagnosed with Type 2 Diabetes Mellitus.

Background: Dynapenia and non-alcoholic fatty liver disease (NAFLD) are common, especially in the middle and advanced-age diabetic male population. We aimed to examine the clinical features, NAFLD severity, and parameters associated with the presence of dynapenia in type 2 diabetes mellitus (T2DM) cases. Material and Methods: One hundred thirty-five male patients diagnosed with T2DM between 45 and 65 years of age were included. Patients were staged by ultrasonography according to NAFLD status. Results: There were significant differences in muscle strength, upper arm circumference, calf circumference, and up-and-go test scores between the mild-moderate-severe and non-NAFLD groups (p < 0.001 for all). The frequency of dynapenia was lower, and arm and calf circumferences were higher in patients without NAFLD. The muscle strength, upper arm circumference, calf circumference, and up-and-go test scores were significantly lower in the dynapenic group compared to the non-dynapenic group (p < 0.005 for all). The prevalence of dynapenia increased along with the increase in NAFLD stages (p < 0.001). Conclusions: We detected a significant association between NAFLD and dynapenia in middle-aged men with T2DM. As muscle strength decreases, the amount of fat in the liver increases, and as the fat in the liver increases, muscle strength decreases.

Are Nonalcoholic Fatty Liver Disease and Bone Mineral Density Associated? - A Cross-Sectional Study Using Liver Biopsy and Dual-Energy X-Ray Absorptiometry.

There is controversy regarding the association between nonalcoholic fatty liver disease (NAFLD) and osteoporosis. Our study aim was to assess bone mineral density (BMD) in patients with biopsy-proven NAFLD and examine if the severity of NAFLD affects BMD. A total of 147 adult women (n= 108) and men (n= 39) aged 18-76 years (mean ± standard deviation [SD] age 45.3 ± 12.5) were recruited in this cross-sectional study and underwent a liver biopsy and dual-energy X-ray absorptiometry (DXA). NAFLD activity score (NAS) based on the degree of steatosis, lobular inflammation and hepatocellular ballooning was used to assess NAFLD severity. The majority of subjects, 53%, had steatosis, 25% had nonalcoholic steatohepatitis (NASH) whereas 23% served as control subjects with no evidence of NAFLD. There were no significant differences in the lumbar spine (1.09 ± 0.12, 1.11 ± 0.18, and 1.12 ± 0.15 g/cm2, p= 0.69, in controls, steatosis, and NASH, respectively) or hip BMD (1.10 ± 0.15, 1.12 ± 0.13, and 1.09 ± 0.13 g/cm2, p= 0.48, in controls, steatosis, and NASH, respectively) between the groups. Adjusting for age, gender, body mass index, and diabetes in multiple regression models did not alter the results. There was no correlation between NAS and neither lumbar spine BMD (r= 0.06, p= 0.471), nor hip BMD (r= -0.03, p= 0.716). In conclusion, BMD was similar across the spectrum of NAFLD in both genders and not related to the severity of the underlying histological lesions, suggesting that neither steatosis nor NASH exerts a detrimental effect on BMD in these relatively young patients. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Orthosiphon aristatus (Blume) Miq Alleviates Non-Alcoholic Fatty Liver Disease via Antioxidant Activities in C57BL/6 Obese Mice and Palmitic-Oleic Acid-Induced Steatosis in HepG2 Cells.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of liver disease. Orthosiphon aristatus (Blume) Miq, a traditional plant in South Asia, has previously been shown to attenuate obesity and hyperglycaemic conditions. Eight weeks of feeding C57BL/6 mice with the standardized O. aristatus extract (400 mg/kg) inhibited the progression of NAFLD. Liver enzymes including alanine aminotransferase and aspartate transaminase were significantly reduced in treated mice by 74.2% ± 7.69 and 52.8% ± 7.83, respectively. Furthermore, the treated mice showed a reduction in serum levels of glucose (50% ± 5.71), insulin (70.2% ± 12.09), total cholesterol (27.5% ± 15.93), triglycerides (63.2% ± 16.5), low-density lipoprotein (62.5% ± 4.93) and atherogenic risk index relative to the negative control. Histologically, O. aristatus reversed hepatic fat accumulation and reduced NAFLD severity. Notably, our results showed the antioxidant activity of O. aristatus via increased superoxide dismutase activity and a reduction of hepatic malondialdehyde levels. In addition, the levels of serum pro-inflammatory mediators (IL-6 and TNFα) decreased, indicating anti-inflammatory activity. The aqueous, hydroethanolic and ethanolic fractions of O. aristatus extract significantly reduced intracellular fat accumulation in HepG2 cells that were treated with palmitic-oleic acid. Together, these findings suggest that antioxidant activities are the primary mechanism of action of O. aristatus underlying the anti-NAFLD effects.

Effect of an obesogenic high-fat and high-sucrose diet on hepatic gene expression signatures in male Collaborative Cross mice.

Nonalcoholic fatty liver disease (NAFLD), the most prevalent chronic liver disease, is characterized by substantial variations in case-level severity. In this study, we used a genetically diverse Collaborative Cross (CC) mouse population model to analyze the global transcriptome and clarify the molecular mechanisms involved in hepatic fat accumulation that determine the level and severity of NAFLD. Twenty-four strains of male CC mice were maintained on a high-fat/high-sucrose (HF/HS) diet for 12 wk, and their hepatic gene expression profiles were determined by next-generation RNA sequencing. We found that the development of the nonalcoholic fatty liver (NAFL) phenotype in CC mice coincided with significant changes in the expression of hepatic genes at the population level, evidenced by the presence of 724 differentially expressed genes involved in lipid and carbohydrate metabolism, cell morphology, vitamin and mineral metabolism, energy production, and DNA replication, recombination, and repair. Importantly, expression of 68 of these genes strongly correlated with the extent of hepatic lipid accumulation in the overall population of HF/HS diet-fed male CC mice. Results of partial least squares (PLS) modeling showed that these derived hepatic gene expression signatures help to identify the individual mouse strains that are highly susceptible to the development of NAFLD induced by an HF/HS diet. These findings imply that gene expression profiling, combined with a PLS modeling approach, may be a useful tool to predict NAFLD severity in genetically diverse patient populations.NEW & NOTEWORTHY Feeding male Collaborative Cross mice an obesogenic diet allows modeling NAFLD at the population level. The development of NAFLD coincided with significant hepatic transcriptomic changes in this model. Genes (724) were differentially expressed and expression of 68 genes strongly correlated with the extent of hepatic lipid accumulation. Partial least squares modeling showed that derived hepatic gene expression signatures may help to identify individual mouse strains that are highly susceptible to the development of NAFLD.

Nonalcoholic fatty liver disease and non-liver comorbidities.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by excess fat accumulation in the liver. It is closely associated with metabolic syndrome, and patients with NAFLD often have comorbidities such as obesity, type 2 diabetes mellitus, and dyslipidemia. In addition to liver-related complications, NAFLD has been associated with a range of non-liver comorbidities, including cardiovascular disease, chronic kidney disease, and sleep apnea. Cardiovascular disease is the most common cause of mortality in patients with NAFLD, and patients with NAFLD have a higher risk of developing cardiovascular disease than the general population. Chronic kidney disease is also more common in patients with NAFLD, and the severity of NAFLD is associated with a higher risk of developing chronic kidney disease. Sleep apnea, a disorder characterized by breathing interruptions during sleep, is also more common in patients with NAFLD and is associated with the severity of NAFLD. The presence of non-liver comorbidities in patients with NAFLD has important implications for the management of this disease. Treatment of comorbidities such as obesity, type 2 diabetes mellitus, and dyslipidemia may improve liver-related outcomes in patients with NAFLD. Moreover, treatment of non-liver comorbidities may also improve overall health outcomes in patients with NAFLD. Therefore, clinicians should be aware of the potential for non-liver comorbidities in patients with NAFLD and should consider the management of these comorbidities as part of the overall management of this disease.

The Association between Coffee Consumption and Non-Alcoholic Fatty Liver Disease: Is there a Protective Role?

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease. Several studies have suggested a protective role of coffee in chronic liver disease, but their results remain controversial. AIM: The purpose of the study was to investigate the association between coffee consumption and the prevalence and severity of NAFLD in a non-diabetic and non-alcoholic population. METHODS: This study involved 157 participants. Cases were defined by the presence of steatosis on liver ultrasound, the severity of which was assessed by the Bright Liver Steatosis Score. Controls were defined by the absence of steatosis on liver ultrasound. All patients with cytolysis and/or cholestasis had an etiological investigation (serologic testing for Hepatitis B virus and hepatitis C virus infection, and autoimmune investigation). All participants underwent liver ultrasound, clinical assessment (blood pressure, waist circumference, and body mass index (BMI)), and biological assessment (Complete Blood Count, lipid profile test, liver function tests, and Fasting Blood Glucose [FBG]). Dietary assessment was conducted using a food frequency questionnaire, coffee consumption was dichotomized into present or absent and then categorized according to the number of cups consumed per day. RESULTS: The study included 94 NAFLD and 63 controls, the two groups were comparable in demographic characteristics. The means of systolic blood pressure, BMI, waist circumference, Aspartate Transaminase, Alanine Transaminase (ALT), Gamma-Glutamyl transferase (GGT), alkaline phosphatase, and FBG were significantly higher in the NAFLD group. The study of the association between coffee consumption and NAFLD showed a significant decrease in the risk of its occurrence (Odds Ratios [OR] = 0.39) and its severity (OR = 0.32) in coffee consumers, mainly in those consuming 3 or more cups. In multivariate analysis, the following factors were associated with increased prevalence of NAFLD: Metabolic syndrome, high mean levels of alkaline phosphatase, GGT, ALT, FBG, BMI, and waist circumference. However, Green tea consumption was not associated with either prevalence or severity of NAFLD (OR = 1.02, p = 0.82). CONCLUSION: Coffee consumption is inversely associated with the prevalence and severity of NAFLD. Further prospective studies are needed to establish a cause-effect relationship between coffee and NAFLD.

Insulin Resistance, but Not Obstructive Sleep Apnea Is Associated with Hepatic Steatosis in Chinese Patients with Severe Obesity

Introduction: Severe obesity is often present with non-alcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA). Emerging researches suggest OSA plays an important role in NAFLD development and progression while the relationship between OSA and NAFLD is still conflicting. The interaction of OSA and NAFLD should be further evaluated as obesity surges. The purpose of this study was to assess the prevalence of OSA and NAFLD in patients with obesity undergoing bariatric surgery and evaluate the association between OSA and severity of NAFLD. Methods: 141 patients with severe obesity undergoing preoperative polysomnography and intraoperative liver biopsy during bariatric surgery were investigated. Clinical, anthropometric variables, liver enzymes, fasting blood glucose, fasting serum insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. The severity of NAFLD was assessed by degree of steatosis, ballooning, intralobular inflammation, and NAFLD activity score. The diagnosis and severity assessment of OSA was based on an apnea/hypopnea index (AHI). Results: OSA was diagnosed in 127 (90.07%), NAFLD in 124 (87.94%), and non-alcoholic steatohepatitis in 72 (51.06%) patients. There was a statistical difference in BMI, waist circumstance, neck circumstance, high-density lipoprotein cholesterol, fasting insulin, and HOMA-IR among the three groups divided by the severity of AHI. In addition, the distribution of hepatic steatosis grades among the three groups was statistically different (p = 0.025). AHI was significantly associated with HOMA-IR and hepatic steatosis when assessing the association between OSA parameters and liver histology in NAFLD (p < 0.05). Patients with steatosis of grades 1–3 had significantly elevated aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, triglycerides, fasting insulin, fasting glucose, HOMA-IR, and AHI compared with the patients with steatosis of grade 0. In a multivariable logistic analysis, the positive association between AHI and hepatic steatosis attenuated after adjusting for HOMA-IR. Conclusion: Prevalence of OSA and NAFLD was high in patients with obesity eligible for bariatric procedures. HOMA-IR, but not AHI, was an independent risk factor for hepatic steatosis in this population.

Obese Patients With Nonalcoholic Fatty Liver Disease Have an Increase in Soluble Plasma CD163 and a Concurrent Decrease in Hepatic Expression of CD163.

Macrophages play an important role in the development of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH). In this study, we investigated the hepatic expression of the macrophage scavenger receptor CD163 and the plasma level of its shed soluble form (sCD163) in patients with obesity and NASH, non-NASH NAFLD (NAFL), or healthy livers (no NAFLD). Paired liver biopsies and plasma samples were collected from 61 patients with obesity (body mass index ≥35). Hepatic expression of CD163 was analyzed by immunohistochemistry and data-independent acquisition mass spectrometry, whilst plasma levels of sCD163 were determined by enzyme-linked immunosorbent assay and data-independent acquisition mass spectrometry. NAFLD stage and activity were assessed using the Kleiner fibrosis and NASH Clinical Research Network (NAS-CRN) scoring system. sCD163 turned out as a promising predictor of NASH with an area under the receiver-operating characteristic curve of 0.78 [0.65;0.92] (P= .0008). sCD163 increased with more severe NAFLD both in univariate (odds ratio [OR]= 3.31[1.80;6.11], P < .001) and multivariable ordinal logistic regression adjusting for NAFLD risk factors (OR= 2.02 [1.03;3.97], P= .042). On the other hand, hepatic expression of CD163 was negatively associated with more severe NAFLD in univariate ordinal logistic regression determined by immunohistochemistry (OR= 0.91[0.84;0.98], P= .015) and proteomics (OR= 0.13[0.02;0.80], P= .028). Taking NAFLD risk factors into account, hepatic expression of CD163 was only associated with the fibrosis stage (OR= 0.01 [0.0003;0.21], P= .004). Accordingly, hepatic CD163 surface expression and sCD163 were negatively correlated (rho=-0.478, P= .0001). An increased plasma sCD163 and a concurrent decreased hepatic expression of CD163 are strongly associated with NAFLD in obese patients.

Helicobacter pylori Infection in Patients with Non Alcoholic Fatty Liver Disease: A Cross-sectional Study

Introduction:Helicobacter pylori (H. pylori) infection is postulated to predispose Non Alcoholic Fatty Liver Disease (NAFLD) through alteration of lipid profile, reduction of adiponectin, insulin resistance, etc. In the setting of increased incidence of NAFLD, the possible therapeutic and preventive implications of an association of H. pylori infection with NAFLD holds interest. Aim: To determine the prevalence of H. pylori infection among NAFLD patients and its association with severity of NAFLD. Materials and Methods: This hospital based cross-sectional study was carried out during July 2019 to December 2021 among 197 patients diagnosed with NAFLD. H. pylori infection was diagnosed by H. pylori specific anti-Immunoglobulin M (IgM) and anti-IgG antibody tests. Descriptive statistics like proportions, mean and standard deviation were used. Chisquare test was used to check for associations of disease severity with H. pylori infection. Results: The study population included 90 females and 107 males. A total of 121 (61.4%) subjects had grade 1 fatty liver, while 46 (23.4%) had grade 2 fatty liver and 30 (15.2%) had grade 3 fatty liver. A total of 125 (63.45%) were H. pylori IgG positive. H. pylori infection positively associated with disease grade, Chronic Liver Disease (CLD) and decompensation (p-value &lt;0.001). Conclusion: The prevalence of H. pylori infection in patients with NAFLD was 63.45% and H. pylori seropositivity was significantly associated with disease severity.

Comparative Analysis of Global Hepatic Gene Expression in Adolescents and Adults with Non-alcoholic Fatty Liver Disease.

To gain insights into the mechanisms underlying distinct nonalcoholic fatty liver disease (NAFLD) histological phenotypes between children and adults, we compared hepatic gene expression profiles associated with NAFLD phenotypes between the two age groups. Histological characteristics of intra-operative liver biopsies from adolescents and adults undergoing bariatric surgery were assessed by the same pathologist using the non-alcoholic steatohepatitis (NASH) Clinical Research Network scoring system. Hepatic gene expression was measured by microarray analysis. Transcriptomic signatures of histological phenotypes between the two groups were compared, with significance defined as p-value <0.05 and a fold change >1.5. In 67 adolescents and 76 adults, distribution of histological phenotypes was: not-NAFLD (controls) 51% vs 39%, NAFL 39% vs 37%, and NASH 10% vs 24%, respectively. There were 279 differentially expressed genes in adolescents and 213 in adults with NAFLD vs controls. In adolescents, transcriptomes for NAFL vs controls, and borderline vs definite NASH were undifferentiable, whereas in adults, NAFL and borderline NASH demonstrated a transcriptomic gradient between controls and definite NASH. When applied to adolescents, significant adult genes discriminated borderline and definite NASH from control and NAFL, but the majority of significant pediatric genes were not portable to adults. Genes associated with NASH in adolescents and adults showed some ontological consistency but notable differences. There is some similarity but major differences in the transcriptomic profiles associated with NAFLD between adolescents and adults with severe obesity. These data suggest different mechanisms contribute to the pathogenesis of NAFLD severity at different stages in life.

Accurate diagnosis of liver diseases through the application of deep convolutional neural network on biopsy images

&lt;abstract&gt; &lt;p&gt;Accurate detection of non-alcoholic fatty liver disease (NAFLD) through biopsies is challenging. Manual detection of the disease is not only prone to human error but is also time-consuming. Using artificial intelligence and deep learning, we have successfully demonstrated the issues of the manual detection of liver diseases with a high degree of precision. This article uses various neural network-based techniques to assess non-alcoholic fatty liver disease. In this investigation, more than five thousand biopsy images were employed alongside the latest versions of the algorithms. To detect prominent characteristics in the liver from a collection of Biopsy pictures, we employed the YOLOv3, Faster R-CNN, YOLOv4, YOLOv5, YOLOv6, YOLOv7, YOLOv8, and SSD models. A highlighting point of this paper is comparing the state-of-the-art Instance Segmentation models, including Mask R-CNN, U-Net, YOLOv5 Instance Segmentation, YOLOv7 Instance Segmentation, and YOLOv8 Instance Segmentation. The extent of severity of NAFLD and non-alcoholic steatohepatitis was examined for liver cell ballooning, steatosis, lobular, and periportal inflammation, and fibrosis. Metrics used to evaluate the algorithms' effectiveness include accuracy, precision, specificity, and recall. Improved metrics are achieved by optimizing the hyperparameters of the associated models. Additionally, the liver is scored in order to analyse the information gleaned from biopsy images. Statistical analyses are performed to establish the statistical relevance in evaluating the score for different zones.&lt;/p&gt; &lt;/abstract&gt;

Prevalence and dynamics of NAFLD-associated fibrosis in people living with HIV in Vienna from first presentation to last follow-up.

Non-alcoholic fatty liver disease (NAFLD) is frequent in people living with HIV (PLWH) and may be aggravated by metabolic comorbidities and antiretroviral therapy (ART)-associated adverse effects. We retrospectively assessed epidemiological, clinical and laboratory parameters and ART regimens at HIV diagnosis (BL) and at last follow-up (FU) in 1458 PLWH without viral hepatitis coinfection attending our HIV clinic in 2014-2016. Fibrosis was non-invasively assessed by the NAFLD fibrosis score (NFS). The median age of subjects was 37.8years, 77.4% were male and 67.2% on ART, median CD4+ count was 356.0cells/µL. At BL, 503 (34.5%) and 20 (1.4%) PLWH had dyslipidemia and diabetes, respectively. According to the NFS 16 (1.3%) showed advanced fibrosis (NFS ≥ 0.676), among which 1 (6.3%) had diabetes, 7 (43.8%) had dyslipidemia, and 5 (31.3%) were on HIV-protease inhibitors (PI). In addition, 191(15.1%) had intermediate NFS results, while fibrosis was ruled out (NFS ≤ 1.455) in 1065 (83.7%) PLWH. After amedian follow-up of 6.3years, 590 (42.8%) had dyslipidemia and 61 (4.4%) had diabetes. Also, 21 (1.6%) showed advanced fibrosis, of which 10 (47.6%) had diabetes, 4 (19.0%) had dyslipidemia, and 9 (42.9%) were on PI-based ART, 223 (17.4%) had intermediate NFS results, while 1039 (81.0%) showed no fibrosis. During FU, advanced NAFLD fibrosis occurred in 1.3-1.6% of PLWH. Dyslipidemia, diabetes, and PI-based ART were associated with advanced NAFLD fibrosis. Prospective investigations of NAFLD severity and risk factors in PLWH are warranted.

Clinical value of thyroid related hormones combined with neutrophil to lymphocyte ratio in patients with nonalcoholic fatty liver disease

In sufferers with nonalcoholic fatty liver disease (NAFLD), the differences of thyroid associated hormones and neutrophil to lymphocyte ratio (NLR) in different liver pathological groups have been compared. Patients with NAFLD diagnosed by liver biopsy in our hospital from July 2012 to February 2019 were selected. All subjects were divided into nonalcoholic steatohepatitis (NASH) team and non-NASH group, no/mild fibrosis group (F0-1) and significant fibrosis group (F2-4). The differences of thyroid related hormones and NLR in these groups were in contrast, respectively. For the TSH, we conducted further evaluation based on gender. The TSH and NLR in NASH patients were significantly higher than non-NASH patients, but there was no considerable difference in free triiodothyronine (FT3) and free thyroxine (FT4) between the 2 groups. In the gender-based subgroup analysis, the variations of TSH between the 2 groups were nonetheless statistically significant (P < .05). The TSH and NLR in the significant fibrosis group were higher than these in the non/mild liver fibrosis group, and the differences were statistically significant (P < .05), but there was no large difference in FT3 and FT4 between the 2 groups (P > .05). In addition, in the gender-based subgroup analysis and further multivariable analysis, the variations of TSH between the 2 groups were still statistically significant (P < .05). In this study, we found that serum thyroid stimulating hormone (TSH) and neutrophil to lymphocyte ratio (NLR) were closely associated to the severity of NAFLD, suggesting that this simple available laboratory index may additionally be incorporated into the future noninvasive diagnostic scoring model to predict the incidence of NASH and the degree of fibrosis.

Preoperative circulating peroxiredoxin 1 levels as a predictor of non-alcoholic fatty liver disease remission after laparoscopic bariatric surgery.

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and insulin resistance and can be improved after bariatric surgery. Circulating Peroxiredoxin 1 (Prdx1) protein was reported to regulate energy metabolism and inflammation. This study aimed to investigate the roles of serum prdx1 in NAFLD patients with obesity undergoing LSG and to develop a prognostic model to predict the remission of severe NAFLD. The data of 93 participants from a tertiary hospital were assessed. Before laparoscopic sleeve gastrectomy (LSG) and three months after LSG, anthropometric parameters, laboratory biochemical data, and abdominal B-ultrasound results were collected, and their hepatic steatosis index (HSI) and triglyceride-glucose index (TyG) were calculated. A NAFLD improvement (NAFLD-I) nomogram prediction model was constructed using the least absolute shrinkage and selection operator (LASSO) regression and multiple regression, and its predictive ability was verified in a validation cohort. The baseline Prdx1 (OR: 0.887, 95% CI: 0.816-0.963, p=0.004), preoperative TyG (OR: 8.207, 95% CI: 1.903-35.394, p=0.005) and HSI (OR: 0.861, 95% CI: 0.765-0.969, p=0.013) levels were independently associated with NAFLD-I at three months after LSG in NAFLD patients with obesity. In the primary and validation cohorts, the area under the receiver operating characteristic (AUC) of the developed nomogram model was 0.891 and 0.878, respectively. The preoperative circulating Prdx1 levels of NAFLD patients with obesity were significantly reduced after LSG (25.32 [18.99-30.88] vs. 23.34 [15.86-26.42], p=0.001). Prdx1 was related to obesity and hepatic steatosis based on correlation analysis. The nomogram based on preoperative serum prdx1, HSI and TyG could be an effective tool for predicting remission of severe NAFLD after LSG.

Increased Intake of Both Caffeine and Non-Caffeine Coffee Components Is Associated with Reduced NAFLD Severity in Subjects with Type 2 Diabetes.

Coffee may protect against non-alcoholic fatty liver disease (NAFLD), but the roles of the caffeine and non-caffeine components are unclear. Coffee intake by 156 overweight subjects (87% with Type-2-Diabetes, T2D) was assessed via a questionnaire, with 98 subjects (all T2D) also providing a 24 h urine sample for quantification of coffee metabolites by LC-MS/MS. NAFLD was characterized by the fatty liver index (FLI) and by Fibroscan® assessment of fibrosis. No associations were found between self-reported coffee intake and NAFLD parameters; however, total urine caffeine metabolites, defined as Σcaffeine (caffeine + paraxanthine + theophylline), and adjusted for fat-free body mass, were significantly higher for subjects with no liver fibrosis than for those with fibrosis. Total non-caffeine metabolites, defined as Σncm (trigonelline + caffeic acid + p-coumaric acid), showed a significant negative association with the FLI. Multiple regression analyses for overweight/obese T2D subjects (n = 89) showed that both Σcaffeine and Σncm were negatively associated with the FLI, after adjusting for age, sex, HbA1c, ethanol intake and glomerular filtration rate. The theophylline fraction of Σcaffeine was significantly increased with both fibrosis and the FLI, possibly reflecting elevated CYP2E1 activity-a hallmark of NAFLD worsening. Thus, for overweight/obese T2D patients, higher intake of both caffeine and non-caffeine coffee components is associated with less severe NAFLD. Caffeine metabolites represent novel markers of NAFLD progression.

Triglyceride to high-density lipoprotein cholesterol ratio is an independent predictor of liver fibrosis among pediatrics non-alcoholic fatty liver disease.

Insulin resistance (IR), one of the key components of the metabolic syndrome, is recognized as the pathophysiological hallmark of non-alcoholic fatty liver disease (NAFLD). This study aims to investigate the relationship between surrogate markers of IR and the severity of NAFLD among overweight or obese children. A total of 56 consecutive children aged 6 to 18 years old were recruited from the pediatric obesity and type 2 diabetes mellitus (T2DM) clinic in University Malaya Medical Centre (UMMC) from 2016 to 2019. Data on anthropometric measurements, clinical components of metabolic syndrome and fasting serum insulin were collected. Triglyceride to high-density lipoprotein cholesterol ratio (TG: HDL-C), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and Single Point Insulin Sensitivity Estimator (SPISE) were calculated. Transient elastography was performed with hepatic steatosis and liver fibrosis assessed by controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. A total of 44 children (78.6%) had liver steatosis and 35.7% had presence of significant liver fibrosis (stage F≥2). Majority (89.3%) are obese and 24 children (42.9%) were diagnosed with metabolic syndrome. Higher number of children with T2DM and significant liver fibrosis were associated with higher tertiles of TG: HDL-C ratio (p<0.05). Top tertile of TG: HDL-C ratio was an independent predictor of liver fibrosis (OR=8.14, 95%CI: 1.24-53.36, p=0.029). ROC analysis showed that the area under the curve (AUC) of HOMA-IR (0.77) and TG: HDL-C ratio (0.71) were greater than that of metabolic syndrome (0.70), T2DM (0.62) and SPISE (0.22). The optimal cut-off values of HOMA-IR and TG: HDL-C ratio for detecting liver fibrosis among children with NAFLD are 5.20 and 1.58, respectively. Children with NAFLD and higher TG: HDL-C ratio are more likely to have liver fibrosis. TG: HDL-C ratio is a promising tool to risk stratify those with NAFLD who are at risk of developing advanced liver disease.

Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in non-alcoholic fatty liver disease

Despite recent progress, non-invasive tests for the diagnostic assessment and monitoring of non-alcoholic fatty liver disease (NAFLD) remain an unmet need. Herein, we aimed to identify diagnostic signatures of the key histological features of NAFLD. Using modified-aptamer proteomics, we assayed 5,220 proteins in each of 2,852 single serum samples from 636 individuals with histologically confirmed NAFLD. We developed and validated dichotomized protein-phenotype models to identify clinically relevant severities of steatosis (grade 0 vs. 1-3), hepatocellular ballooning (0 vs. 1 or 2), lobular inflammation (0-1 vs. 2-3) and fibrosis (stages 0-1 vs. 2-4). The AUCs of the four protein models, based on 37 analytes (18 not previously linked to NAFLD), for the diagnosis of their respective components (at a clinically relevant severity) in training/paired validation sets were: fibrosis (AUC 0.92/0.85); steatosis (AUC 0.95/0.79), inflammation (AUC 0.83/0.72), and ballooning (AUC 0.87/0.83). An additional outcome, at-risk NASH, defined as steatohepatitis with NAFLD activity score ≥4 (with a score of at least 1 for each of its components) and fibrosis stage ≥2, was predicted by multiplying the outputs of each individual component model (AUC 0.93/0.85). We further evaluated their ability to detect change in histology following treatment with placebo, pioglitazone, vitamin E or obeticholic acid. Component model scores significantly improved in the active therapies vs. placebo, and differential effects of vitamin E, pioglitazone, and obeticholic acid were identified. Serum protein scanning identified signatures corresponding to the key components of liver biopsy in NAFLD. The models developed were sufficiently sensitive to characterize the longitudinal change for three different drug interventions. These data support continued validation of these proteomic models to enable a "liquid biopsy"-based assessment of NAFLD. Not applicable. An aptamer-based protein scan of serum proteins was performed to identify diagnostic signatures of the key histological features of non-alcoholic fatty liver disease (NAFLD), for which no approved non-invasive diagnostic tools are currently available. We also identified specific protein signatures related to the presence and severity of NAFLD and its histological components that were also sensitive to change over time. These are fundamental initial steps in establishing a serum proteome-based diagnostic signature of NASH and provide the rationale for using these signatures to test treatment response and to identify several novel targets for evaluation in the pathogenesis of NAFLD.

Risk factors in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, with a global prevalence estimated at approximately 25%. NAFLD is also the leading cause of liver cirrhosis, hepatocellular carcinoma, and death. Additionally, the risk of cardiovascular disease increases with greater NAFLD severity. The liver- and cardiovascular disease-related mortality incident rate ratios among the NAFLD population were 0.77 and 4.79 per 1,000 person-years, respectively. We intend to discuss the risk factors associated with NAFLD in terms of development and progression. Obesity or higher body mass index is closely associated with NAFLD in a dose-dependent manner, but growing evidence suggests that central obesity plays a more important role in the development of NAFLD. Saturated fat and fructose have been reported to be closely related to NAFLD. Fructose intake promotes lipogenesis and impairs mitochondria fat oxidation. The presence of type 2 diabetes is the most powerful predictive risk factor for hepatic fibrosis in patients with NAFLD. Single nucleotide polymorphism is not only associated with the prevalence of NAFLD but also associated with increased liver disease mortality. Obstructive sleep apnea, intestinal dysbiosis, and sarcopenia are associated with the development of NAFLD.

Association of complement components with the risk and severity of NAFLD: A systematic review and meta-analysis.

It is generally believed that complement system is strongly associated with the risk of nonalcoholic fatty liver disease (NAFLD). However, complement system contains a variety of complement components, and the relationship between complement components and the risk and severity of NAFLD is inconsistent. The aim of this meta-analysis was to evaluate the association of complement components with the risk and severity of NAFLD. We searched PubMed, Embase, Cochrane Library, Google Scholar, Scopus, and ZhiWang Chinese databases from inception to May 2022 for observational studies reporting the risk of NAFLD with complement components. Random-effects meta-analysis was used to obtain pooled estimates of the effect due to heterogeneity. We identified 18 studies with a total of 18560 included subjects. According to recent studies, levels of complement component 3 (C3) (mean difference (MD): 0.43, 95% confidence interval (CI) 0.26-0.60), complement component 4 (C4) (MD: 0.04, 95% CI 0.02-0.07), complement component 5(C5) (MD: 34.03, 95% CI 30.80-37.27), complement factor B (CFB) (MD: 0.22, 95% CI 0.13-0.31) and acylation stimulating protein (ASP) (standard mean difference (SMD): 5.17, 95% CI 2.57-7.77) in patients with NAFLD were significantly higher than those in the control group. However, no statistical significance was obtained in complement factor D (CFD) levels between NAFLD and non-NAFLD (MD=156.51, 95% CI -59.38-372.40). Moreover, the levels of C3, C5, CFB, and ASP in patients with moderate and severe NAFLD were significantly higher than those in patients with mild NAFLD. Except for C4 and CFD, the included studies did not explore the changes in the severity of NAFLD according to the concentration of C4 and CFD. This meta-analysis demonstrates that an increase in complement components including C3, C5, CFB, and ASP is associated with an increased risk and severity of NAFLD, indicating that they may be good biomarkers and targets for the diagnosis and treatment of NAFLD. PROSPERO [https://www.crd.york.ac.uk/PROSPERO/], identifier CRD42022348650.