Severity Of Nonalcoholic Fatty Liver Disease Research Articles

Plasma ceramides are associated with MRI-based liver fat content but not with noninvasive scores of liver fibrosis in patients with type 2 diabetes

BackgroundThere is growing evidence that ceramides play a significant role in the onset and progression of non-alcoholic fatty liver disease (NAFLD), a highly prevalent condition in patients with type 2 diabetes associated with hepatic and cardiovascular events. However, the relationship between plasma ceramide levels and NAFLD severity in type 2 diabetes remains unclear. The main purpose of the present study was to investigate whether circulating levels of ceramides in patients with type 2 diabetes are associated with liver steatosis assessed by the highly accurate magnetic resonance imaging proton density fat fraction (MRI-PDFF). The secondary objective was to assess the relationship between plasma ceramides and noninvasive scores of liver fibrosis.MethodsIn this cross-sectional single-center study, plasma concentrations of 7 ceramides were measured by liquid chromatography-mass spectrometry in 255 patients with type 2 diabetes (GEPSAD cohort). Liver fat content was assessed by MRI-PDFF, and noninvasive scores of liver fibrosis (i.e. Fibrosis-4 index, NAFLD Fibrosis Score, FibroTest® and Fibrotic NASH Index) were calculated. A validation cohort of 80 patients with type 2 diabetes was also studied (LIRA-NAFLD cohort).ResultsLiver steatosis, defined as a liver fat content > 5.56%, was found in 62.4 and 82.5% of individuals with type 2 diabetes in the GEPSAD and LIRA-NAFLD cohorts, respectively. In GEPSAD, MRI-PDFF-measured liver fat content was positively associated with plasma levels of total ceramides (r = 0.232, p = 0.0002), and 18:0, 20:0, 22:0 and 24:0 ceramides in univariate analysis (p ≤ 0.0003 for all). In multivariate analysis, liver fat content remained significantly associated with total ceramides (p = 0.001), 18:0 (p = 0.006), 22:0 (p = 0.0009) and 24:0 ceramides (p = 0.0001) in GEPSAD, independently of age, diabetes duration, body mass index and dyslipidemia. Overall, similar relationship between plasma ceramides and liver fat content was observed in the LIRA-NAFLD validation cohort. No significant association was found between plasma ceramides and noninvasive scores of fibrosis after adjustment for age in both cohorts.ConclusionsPlasma ceramide levels are associated with liver steatosis in patients with type 2 diabetes, independently of traditional risk factors for NAFLD. The independent association between plasma ceramides and liver steatosis adds new insights regarding the relationship between ceramides and NAFLD in type 2 diabetes.

Abstract 12321: Discordant Association of Nonalcoholic Fatty Liver Disease With Lipoprotein(a) and Markers of Atherogenic Dyslipidemia

Background: Nonalcoholic fatty liver disease (NAFLD) is associated with atherogenic dyslipidemia and an increased risk of cardiovascular events. Previous studies have suggested a paradoxical inverse relationship between NAFLD severity and Lp(a) level, an independent cardiovascular risk factor. However, contemporary data in patients with biopsy-proven NAFLD in the U.S. are lacking. Hypothesis: NAFLD severity on liver biopsy has a discordant association with Lp(a) and other markers of atherogenic dyslipidemia. Methods: Lp(a), traditional lipid profile, apolipoproteins, and nuclear magnetic resonance-based lipoprotein particle concentration were measured in 151 patients with NAFLD. Levels were compared between those with nonalcoholic fatty liver (NAFL) on histology and non-alcoholic steatohepatitis (NASH), the clinically aggressive NAFLD variant. Results: Median age was 55 [48, 62] years, 67% of patients were women, 83% were White, 43% had NAFL, and 57% had NASH. Demographic characteristics were similar among those with NAFL and NASH. Triglyceride level was higher and High-Density Lipoprotein-cholesterol (HDL-C) was lower among those with NASH as compared with NAFL. Circulating concentration of two key markers of atherogenic dyslipidemia, Apolipoprotein-B (apoB) and Low-Density Lipoprotein particle concentration (LDL-P) was 9% and 17% higher in the NASH group as compared with NAFL, respectively. Contrastingly, Lp(a) concentration was 50% lower in NASH relative to NAFL group (Figure). Hepatocyte ballooning, lobular inflammation, and fibrosis on histology were inversely associated with Lp(a) concentration, while steatosis severity was not. Conclusions: NAFLD severity has a discordant association with Lp(a) and markers of atherogenic dyslipidemia. The mechanistic basis of this relationship may have implications for prognosticating cardiovascular disease risk and determining the safety of targeted Lp(a) lowering in patients with NAFLD.

Food Insecurity and Pediatric Nonalcoholic Fatty Liver Disease Severity

ObjectiveTo determine the association between food insecurity and pediatric nonalcoholic fatty liver disease (NAFLD). MethodsCross-sectional study of patients < 21 years of age with histologically confirmed NAFLD. The Household Food Security Survey Module was administered to determine food insecurity status. Skin lipidomics were performed to explore pathophysiologic mechanisms. ResultsSeventy-three patients with histologically confirmed NAFLD completed the Household Food Security Survey Module. Of these, the majority were male (81%) and non-Hispanic (53%), with a mean age at biopsy of 13±3 years. Food insecurity was seen in 42% (n=31). Comparison of features between food insecure and food secure subgroups revealed no differences in sex, ethnicity, BMI z-score, aminotransferases, or histologic severity. However, children experiencing food insecurity presented on average two years before their food secure counterparts (12.3 ± 3.0 vs. 14.4 ± 3.6 years, p = 0.015). A subset of 31 patients provided skin samples. Skin lipidomics revealed that food insecurity was associated with down-regulated features from the lipoamino acid class of lipids, previously linked to inflammation and adipocyte differentiation. ConclusionsFood insecurity is highly prevalent in children with NAFLD and is associated with earlier presentation. Lipidomic analyses suggest a possible pathophysiologic link that warrants further exploration.

Discordant association of nonalcoholic fatty liver disease with lipoprotein(a) and markers of atherogenic dyslipidemia

Nonalcoholic fatty liver disease (NAFLD) is associated with atherogenic dyslipidemia and an increased risk of cardiovascular events. Previous studies have suggested an inverse relationship between NAFLD severity and lipoprotein(a) [Lp(a)] level, but contemporary data from the U.S. are lacking. Lp(a), lipid profile, apolipoproteins, and nuclear magnetic resonance-based lipoprotein particle concentrations were measured in 151 patients with biopsy-proven NAFLD. Levels were compared between those with nonalcoholic fatty liver (NAFL) on histology and non-alcoholic steatohepatitis (NASH). Median age was 55 [48, 62] years, 67% of patients were women, 83% were White, 43% had NAFL, and 57% had NASH. Triglyceride level was higher and high-density lipoprotein-cholesterol (HDL-C) was lower among those with NASH as compared with NAFL. Circulating apolipoprotein-B (ApoB) and low-density lipoprotein particle concentration (LDL-P) were 9% and 17% higher in the NASH group as compared with NAFL, respectively. Contrastingly, Lp(a) concentration was 50% lower in NASH relative to NAFL group. Hepatocyte ballooning, lobular inflammation, and fibrosis on histology were inversely associated with Lp(a) concentration. NAFLD severity has a discordant association with Lp(a) and other markers of atherogenic dyslipidemia. This relationship may have implications for prognosticating cardiovascular disease risk in patients with NAFLD.

A lipidomic approach to bisphenol F-induced non-alcoholic fatty liver disease-like changes: altered lipid components in a murine model.

Bisphenol A (BPA), a typical environmental endocrine disruptor, is an "obesogen" that can induce lipid accumulation in the liver. Highly similar in structure to BPA, bisphenol F (BPF) is becoming the dominant BPA substitute on the market, which attracts more and more attention due to its potential adverse effects. Recently, BPF exposure is found to cause non-alcoholic fatty liver disease (NAFLD)-like changes; however, the underlying toxic effects remain poorly understood. Therefore, in the current study, we focused on BPF-mediated lipid homeostasis, especially the alterations of lipid components and metabolism. In human serum, the BPF levels in healthy controls and NAFLD patients were assessed by ELISA, and BPF-induced disturbance of lipid metabolism was evaluated in mouse model via non-targeted lipomic methods with ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. It suggested that BPF exposure was positively correlated with NAFLD severity and triglyceride level in patients. Based on the relationships, lipid metabolites were assessed in mouse livers between control and BPF-treated group, and it revealed that twenty-six lipid metabolites (including phospholipids, sphingolipids, and glycerides) were significantly changed in mouse livers. Phosphatidylcholine, phosphatidylethanolamine, and diglyceryl ester levels were lower than those in the control mice; hexose ceramide content in sphingolipids markedly increased in BPF-treated mouse livers. Noteworthily, the glycerophospholipid metabolic pathway was found to be the most pronounced in BPF-induced disturbance of lipid metabolism. Therefore, the current study, for the first time, is deciphering the BPF-induced lipid metabolic disturbance, which may provide novel intervention strategies for BPF-induced NAFLD-like changes.

Sex-specific relationship between non-alcoholic fatty liver disease and amyloid-β in cognitively unimpaired individuals.

Non-alcoholic fatty liver disease (NAFLD) is known to be associated with a high risk of clinically diagnosed Alzheimer's disease (AD). Additionally, the prevalence of NAFLD and AD is higher in elderly females than in males. However, a sex-specific association between NAFLD and amyloid-beta (Aβ) deposition remains unclear. Therefore, we investigated the sex-specific relationship between NAFLD and Aβ deposition in a large-sized cohort of cognitively unimpaired (CU) individuals. We enrolled 673 (410 [60.9%] females and 263 [39.1%] males) CU individuals aged ≥45 years who underwent Aβ positron emission tomography (PET). The presence of NAFLD, assessed using the hepatic steatosis index, and the severity of NAFLD, assessed using the Fibrosis-4 index, were considered predictors. Aβ deposition on PET was considered as an outcome. Females had a higher frequency of NAFLD than males (48 and 23.2%, p < 0.001). Among females, the presence of NAFLD (β = 0.216, p < 0.001) was predictive of increased Aβ deposition, whereas among males, the presence of NAFLD (β = 0.191, p = 0.064) was not associated with Aβ deposition. Among females, the presence of NAFLD with low (β = 0.254, p = 0.039), intermediate (β = 0.201, p = 0.006), and high fibrosis (β = 0.257, p = 0.027) was predictive of increased Aβ deposition. Aβ deposition also increased as the severity of NAFLD increased in females (p for trend = 0.001). We highlight the marked influence of NAFLD and its severity on the risk of Aβ deposition in relation to sex. Furthermore, our findings suggest that sex-specific strategies regarding the management of NAFLD are necessary for the prevention of Aβ deposition.

Lack of association between nonalcoholic fatty liver disease and intracerebral hemorrhage: A community-based cohort study

BackgroundThe association between nonalcoholic fatty liver disease (NAFLD) and intracerebral hemorrhage (ICH) remains unclear. This study aimed to investigate whether NAFLD and its severity predict incident ICH. MethodsParticipants free of other liver diseases, prior stroke, myocardial infarction, cancer, or alcohol abuse in the Kailuan cohort were enrolled in this study. Abdominal ultrasonography was used to diagnose NAFLD and assess its severity. Participants were stratified into different groups including nonfatty liver, mild, moderate and severe NAFLD. Multivariable Cox proportional hazards regression models were used to evaluate the hazard ratios (HRs) and 95% CIs of ICH events in the 11-year follow-up. ResultsA total of 77,461 participants were enrolled in our study. Among them, NAFLD was diagnosed in 23,890 (30.83 %) participants, including 15,581 (20.11 %) with mild NAFLD, 6839 (8.83 %) with moderate NAFLD and 1470 (1.90 %) with severe NAFLD. We documented 692 ICH events during 848,579 person years of follow-up. Patients with more severe NAFLD tended to be older, had higher levels of BMI, higher proportions of hypertension, diabetes and other known risk factors for cerebrovascular disease. However, there was no significant associations between NAFLD, its severity and incident ICH events. Relative to nonfatty liver participants, the HRs for participants with mild NAFLD, moderate and severe NAFLD were 0.98 (95 % CI, 0.80 to 1.20), 1.19 (95 % CI, 0.92 to 1.54) and 1.29 (95 % CI, 0.81 to 2.06), respectively. ConclusionsNAFLD and its severity did not appear to be significantly associated with ICH after adjustment for potential risk factors.

Mechanisms Behind NAFLD: a System Genetics Perspective.

To summarize the key factors contributing to the onset and progress of nonalcoholic fatty liver disease (NAFLD) and put them in a system genetics context. We particularly focus on how genetic regulation of hepatic lipids contributes to NAFLD. NAFLD is characterized by excessive accumulation of fat in the liver. This can progress to steatohepatitis (inflammation and hepatocyte injury) and eventually, cirrhosis. The severity of NAFLD is determined by a combination of factors including obesity, insulin resistance, and lipotoxic lipids, along with genetic susceptibility. Numerous studies have been conducted on large human cohorts and mouse panels, to identify key determinants in the genome, transcriptome, proteome, lipidome, microbiome and different environmental conditions contributing to NAFLD. We review common factors contributing to NAFLD and put them in a systems genetics context. In particular, we describe how genetic regulation of liver lipids contributes to NAFLD. The combination of an unhealthy lifestyle and genetic predisposition increases the likelihood of accumulating lipotoxic specie lipids that may be one of the driving forces behind developing severe forms of NAFLD.

THU146 Triglyceride Glucose Index Is Superior To The Homeostasis Model Assessment Of Insulin Resistance For Predicting Severity Of Nonalcoholic Fatty Liver Disease In Korean Children And Adolescents

Abstract Disclosure: J. Yoon: None. E. Kim: None. Background: Triglyceride glucose (TyG) index is known as a reliable insulin resistance surrogate marker to identify non-alcoholic fatty liver disease (NAFLD). Ultrasonographic fatty liver indicator (US-FLI) is proposed as a non-invasive, semi-quantitative method for predicting hepatitis in patients with NAFLD and accurately identifies histological severity. Few studies have compared the TyG index to homeostasis model assessment of insulin resistance (HOMA-IR) in the detection of NAFLD in children and adolescents. Additionally, there were no studies comparing the ability of TyG index and HOMA-IR to assess the severity of NAFLD. Objects: Therefore, we investigated the relationship between TyG index and NAFLD compared to HOMA-IR in identifying and assessing the severity of NAFLD in children and adolescents. Methods: Alanine aminotransferase (ALT) was used as the screening method for NAFLD (&amp;gt;26IU/L in boys and &amp;gt;22IU/L in girls), and US-FLI was performed on children who met these criteria. The US-FLI is a scoring system ranging 2-8 that evaluates based on intensity of liver/kidney contrast, posterior attenuation of ultrasound beam, vessel blurring, difficult visualization of gallbladder wall, difficult visualization of the diaphragm and areas of focal sparing. NAFLD is diagnosed by the minimum score ≥2. Healthy children of normal weight (body mass index 5-85th percentile) without metabolic comorbidities and no steatosis on ultrasound participated as a control group. TyG index was calculated as ln(fasting triglyceride (TG) [mg/dL] × fasting glucose [mg/dL]/2). Results: A total of 130 NAFLD patients (90 boys and 40 girls) included in this study, with mean age of 11.5±2.29 years. The control group consisted of a total of 28 subjects (17 boys and 11 girls) with mean age of 8.39±1.60 years. The US-FLI was significantly correlated with TyG index (r=0.264, p=0.003) but not with HOMA-IR after controlling for sex, age, and BMI. Multiple linear regression analysis showed that TyG index were significantly associated with US-FLI (β=0.202, p=0.002) not with HOMA-IR after controlling for sex, age, and BMI. The TyG index was superior to HOMA-IR in its ability to detect the severity of NAFLD in US-FLI ≥4, ≥5, and ≥6. Conclusions: Both TyG index and HOMA-IR were useful for detecting pediatric NAFLD. However, the TyG index was useful for detecting the severity of NAFLD, whereas HOMA-IR was not. Therefore, we propose to use the TyG index to predict and evaluate the severity of NAFLD in children. Presentation: Thursday, June 15, 2023

THU140 Triglyceride Glucose-body Mass Index Is A Reliable Surrogate Marker To Predict Non-alcoholic Fatty Liver Disease In Children And Adolescents

Abstract Disclosure: J. Yoon: None. K. Yi: None. Background: The triglyceride glucose (TyG) index is significantly associated with the presence of nonalcoholic fatty liver disease (NAFLD) and is a reliable insulin resistance (IR) surrogate marker. TyG index combined with body mass index (BMI) were reported to be superior to TyG index alone in predicting NAFLD in youths. Ultrasound fatty liver indicator (US-FLI) is proposed as a non-invasive, semi-quantitative method for predicting hepatitis in children with NAFLD. Objects: In this study, TyG-BMI detection ability was evaluated in children and adolescents with NAFLD diagnosed by US-FLI and compared with TyG index. We also analyzed the association between TyG-BMI and severity of NAFLD according to the US-FLI scores. Methods: Alanine aminotransferase (ALT) was used as the screening method for NAFLD (&amp;gt;26IU/L in boys and &amp;gt;22IU/L in girls), and US-FLI was performed on children who met these criteria. The US-FLI is a scoring system ranging 2-8 that evaluates based on intensity of liver/kidney contrast, posterior attenuation of ultrasound beam, vessel blurring, difficult visualization of gallbladder wall, difficult visualization of the diaphragm and areas of focal sparing. NAFLD is diagnosed by the minimum score ≥2. Healthy children of normal weight (body mass index 5-85th percentile) without metabolic comorbidities and no steatosis on ultrasound participated as a control group. TyG index was calculated as ln(fasting triglyceride (TG) [mg/dL] × fasting glucose [mg/dL]/2), and TyG-BMI were calculated as TyG × BMI. The diagnostic value of TyG-BMI for NAFLD detection was evaluated based on area under the receiver operating characteristic curve (AUC). Results: A total of 130 NAFLD patients (90 boys and 40 girls) included in this study, with mean age of 11.5±2.29 years. The control group consisted of a total of 28 subjects (17 boys and 11 girls) with mean age of 8.39±1.60 years. The TyG-BMI was significantly correlated with AST (r=0.282, p=0.005), ALT (r=0.395, p&amp;lt;0.001), HOMA-IR (r=0.444, p&amp;lt;0.001), and US-FLI (r=0.557, p&amp;lt;0.001) after controlling for sex and age. Multiple linear regression analysis showed that TyG-BMI were significantly associated with ALT (β=0.156, p=0.024), HOMA-IR (β =0.247, p&amp;lt;0.001), US-FLI (β=0.366, p&amp;lt;0.001) after adjusting for confounders. TyG-BMI was independent risk factor for NAFLD (odds ratio: 1.13, 95% confidence interval: 1.041-1.228) after controlling sex and age. In the receiver operating characteristic analysis, the TyG–BMI index (AUC=0.994, p&amp;lt;0.001) showed a better performance for detection of NAFLD than the TyG index (AUC=0.834, p&amp;lt;0.001). Conclusions: TyG-BMI is associated with insulin resistance and severity of US-FLI in NAFLD. In addition, TyG-BMI was superior to TyG index alone in detecting NAFLD. TyG-BMI is expected to be useful in detecting NAFLD and predicting disease progression in children and adolescents. Presentation: Thursday, June 15, 2023

THU585 Non-alcoholic Fatty Liver Disease (NAFLD), A Silent But Emerging Problem In Type 1 Diabetes

Abstract Disclosure: A. Taiwo: None. R. Merill: None. L. Wendt: None. D. Pape: None. H. Thakker: None. N. Pothireddy: None. B. Carlson: None. A. Sanchez: None. P. Ten Eyck: None. D. Jalal: None. A. Dokun: None. E. Taylor: None. W. Sivitz: None. Background: Non-alcoholic liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Risk factors include type 2 diabetes, insulin resistance and obesity. Although NAFLD has been widely studied in persons with type 2 diabetes, far less in known about the pathogenesis and severity of NAFLD in type 1 diabetes. Objective: The goal of this study was to understand the metabolic perturbations that contribute to the pathogenesis of NAFLD in type 1 diabetes. Study Design: We conducted a cross-sectional study of 30 participants with type1 diabetes recruited from our institutional diabetes clinic. To assess liver fat content and stiffness, a FibroScan was done. Based on the results, participants were stratified into a case group (evidence of NAFLD) or control group (no evidence of NAFLD). All participants had fasting plasma drawn to determine metabolites. Gas-Chromatography Mass Spectrometry was used for metabolomic analyses and Liquid Chromatography Mass Spectrometry for lipidomic and acylcarnitines analyses. Results: Sixteen of 30 participants were classified as cases and 14 as controls. Cases had higher BMI (P=0.001) and were taking higher daily insulin doses than controls (P=0.008). Metabolomic analyses revealed that cases had elevated levels of glutamate (P=0.001), alanine (P=&amp;lt;0.001), pyruvate (P=&amp;lt;0.001), phenylalanine (P = 0.005), lactate (P=0.019) and anthranilic acid (P=0.029). Lipidomics revealed that, cases had elevated ceramides (P= 0.02), diacylglycerol (P=0.0003) and triacylglycerol (P=0.0003). The acylcarnitine, isovalerylcarnitine (CAR.5.0) a metabolite of isoleucine catabolism, was elevated in the cases (P = 0.010). Pathway enrichment analysis revealed, phenylalanine and tyrosine metabolism, tryptophan metabolism, glucose-alanine cycle, glutamate metabolism and glutathione metabolism were significantly enriched in the cases. Conclusion: We observed evidence of elevated metabolite levels involved in gluconeogenesis, glucose-alanine metabolism, energy metabolism, insulin resistance, and dysfunctional fat synthesis in the cases compared to controls. Our cases had some features similar to Type 2 diabetes with NAFLD, with evidence of elevated levels of aromatic amino acids, ceramides, diacylglycerol and triacylglycerol. However unlike Type 2 diabetes, there was no elevation of branched-chain amino acids levels. Presentation: Thursday, June 15, 2023

THU312 The Type 1 Diabetes Susceptible LEW.1WR1 Rat Develops Insulin Resistance And Severe Non-alcoholic Fatty Liver Disease

Abstract Disclosure: S.T. Love-Rutledge: None. M. Wimalarathne: None. L.D. Mercado: None. A. Smiley: None. C. Apperson: None. Q.C. Vidal: None. A subpopulation of type 1 diabetes patients develop the pathophysiological parameters to be termed double diabetes. This patient population often develops obesity, non-alcoholic fatty liver disease, and other hallmarks of insulin resistance. The LEW.1WR1 rat is a type 1 diabetes susceptible rodent with hyperinsulinemia that has shown signs of fatty liver infiltration1,2. We hypothesized that LEW.1WR1 rats would develop insulin resistance and severe nonalcoholic fatty liver disease due to its increased circulating insulin and predisposition to autoimmune disease. LEW.1WR1 rats and Wistar Furth rats were used for the 18-week long experiment. Peripheral insulin sensitivity was evaluated using insulin tolerance tests at weeks 11 and 17 showing worsening insulin sensitivity as evidenced by the gradual slope compared to the steep slope of the Wistar Furth rats. HOMA-IR values support LEW.1WR1 rats develop worsening insulin sensitivity and are insulin resistant at week 23 of the experiment (2.613± 0.796, p &amp;lt; 0.0001). Terminal liver mass confirmed increased liver mass normalized to body mass and liver triglyceride levels suggested increased ectopic lid accumulation in the liver (Liver Mass 2.65% ±0.32 p = 0.0005 and triglyceride levels 192.8 ± 21.85 mg/dL, p = 0.034). The H&amp;E-stained digital liver slides were scored for liver ballooning, steatosis, and markers of inflammation. Fibrosis and terminal circulating cytokines were also measured to assess severity of condition. While both groups showed increased steatosis and injury ballooning, trichrome blue staining and inflammatory cytokines verify the severity of disease in the LEW.1WR1 rats. LEW rats have increased fibrosis area and high serum TNF-α, IFN-, MCP-1 levels. As hypothesized, we observed that LEW.1WR1 rats show characteristics of insulin resistance and malignant nonalcoholic fatty liver disease development.

FRI591 Association Of TSH Levels And NAFLD Severity In Children And Adolescents

Abstract Disclosure: M. Untalan: None. N.A. Crimmins: None. A. Mencin: None. K. Yates: None. X. Stavra: None. V. Thaker: None. Background: Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation and is now the most common form of chronic liver disease in children and adolescents. Recent studies have indicated an association between subclinical hypothyroidism (SH) and NAFLD. An underactive thyroid gland produces insufficient T3 and T4 involved in hepatic fat metabolism that could contribute to NAFLD. While increased TSH has been documented in individuals with NAFLD, its independent role with NAFLD disease severity is yet to be clarified. Objective: To study the relationship of TSH levels and the severity of NAFLD/NASH, as well as determine whether changes in TSH levels are associated with changes in NAFLD/NASH among children. Methods: This retrospective study used data from two cohorts within the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). TSH, free and total T4, total T3, TPO antibodies and thyroglobulin (TBG) levels were assessed in samples obtained first at baseline and then at 52-96 weeks. Individuals with overt hypothyroidism, abnormal TPO antibody levels, and those receiving thyroid treatment were excluded from analysis. SH was defined as TSH &amp;gt; 4.4 mIU/L. Linear and multinomial regression models were used to identify the association between TSH, SH and NAFLD severity measured by NAFLD activity score (NAS), fibrosis stage, steatosis level, lobular and portal inflammation and ballooning while adjusting for potential confounders (sex, age, race, BMI-z, HOMA-IR and non-HDL levels). Longitudinal analysis was conducted by mixed-effects model. Analyses were performed with SAS and R statistical software. Results: 218 individuals and 421 observations were included in the cross-sectional and longitudinal analyses, respectively. Children with more severe grades of steatosis were more likely to be younger (p = 0.03) and male (p = 0.02). At baseline, TSH was not significantly associated with any NAFLD histological measures. Longitudinal analyses revealed a positive association of change in TSH and steatosis level after adjusting for covariates, and follow-up time (p = 0.03). Change in SH was associated with change in fibrosis stage (p = 0.01). Adding HOMA-IR and non-HDL levels to the models did not change this relationship. The positive relationship of total T3 and T4 with NAS was explained by TBG. Conclusion: In a large cohort of pediatric patients with biopsy-confirmed NAFLD, high TSH levels correlated with increasing steatosis grade and NAS, and SH with increased liver fibrosis. Markers of impaired thyroid function may help predict disease severity in pediatric patients with NAFLD. Presentation: Friday, June 16, 2023

THU139 The Triglyceride-glucose Index Combined With Alanine Aminotransferase Is A Superior Predictor Of The Severity Of Nonalcoholic Fatty Liver Disease In Children And Adolescents

Abstract Disclosure: J. Yoon: None. I. Hwang: None. Background: The triglyceride–glucose (TyG) index is significantly associated with the presence of nonalcoholic fatty liver disease (NAFLD). Alanine aminotransferase (ALT) has been commonly used to screen for NAFLD. Ultrasound fatty liver indicator (US-FLI) is proposed as a non-invasive, semi-quantitative method for predicting NAFLD and accurately identifies histological severity. Objects: We hypothesized that the combination of TyG and ALT would increase the sensitivity and specificity in determining the severity of NAFLD. We evaluated the usefulness of a newly proposed TyG-ALT index for differentiating NAFLD severity and compared it with TyG index. Methods: ALT was used as the screening method for NAFLD (&amp;gt;26 IU/L in boys and &amp;gt;22 IU/L in girls), and the US-FLI was performed on children who met these criteria. US-FLI is a new scoring system ranging 2-8 based on the intensity of liver/kidney contrast, posterior attenuation of ultrasound beam, vessel blurring, difficult visualization of gallbladder wall, difficult visualization of the diaphragm and areas of focal sparing. NAFLD is diagnosed by the minimum score ≥2. The TyG index and the TyG–ALT index were calculated as follows: TyG index=ln(fasting TG [mg/dL]×fasting glucose [mg/dL]/2) and TyG–ALT index= ln(fasting triglyceride [mg/dL]×fasting glucose [mg/dL]×ALT [IU/L]/2). Healthy children of normal weight (body mass index 5-85th percentile) without metabolic comorbidities and no steatosis on ultrasound participated as a control group. Results: A total of 130 NAFLD patients (90 boys and 40 girls) included in this study, with mean age of 11.5±2.29 years. The control group consisted of a total of 28 subjects (17 boys and 11 girls) with mean age of 8.39±1.60 years. Multiple linear regression analysis showed that TyG-ALT index were significantly associated with US-FLI (β=0.356, p&amp;lt;0.001) after controlling for sex, age, and BMI. TyG-ALT index was independent risk factor for NAFLD (odds ratio: 4.218, 95% confidence interval: 1.366-13.020) after controlling for sex, age, and BMI. In the receiver operating characteristic analysis, the area under the curve (AUC) of TyG index was 0.681(p&amp;lt;0.001), 0.681(p&amp;lt;0.001), and 0.782(p&amp;lt;0.001), and AUC of TyG-ALT index was 0.797, (p&amp;lt;0.001), 0.797(p&amp;lt;0.001), and 0.813(p&amp;lt;0.001) in US-FLI ≥4, ≥5, and ≥6, respectively. Conclusions: The TyG–ALT index showed consistently superior detection ability than the TyG index at all severity levels of NAFLD. Further studies are needed to determine its potential role as a noninvasive method for NAFLD screening. Presentation: Thursday, June 15, 2023

Serum metabolomic profiling unveils distinct sex-related metabolic patterns in NAFLD.

Obesity poses an increased risk for the onset of Nonalcoholic fatty liver disease (NAFLD). The influence of other factors, such as sex in the incidence and severity of this liver disease has not yet been fully elucidated. Thus, we aimed to identify the NAFLD serum metabolic signatures associated with sex in normal, overweight and obese patients and to associate the metabolite fluctuations across the increasing liver steatosis stages. Using nuclear magnetic resonance (NMR) serum samples of 210 NAFLD cases and control individuals diagnosed with liver U/S, our untargeted metabolomics enquiry provided a sex distinct metabolic bouquet. Increased levels of alanine, histidine and tyrosine are associated with severity of NAFLD in both men and women. Moreover, higher serum concentrations of valine, aspartic acid and mannose were positively associated with the progression of NAFLD among the male subjects, while a negative association was observed with the levels of creatine, phosphorylcholine and acetic acid. On the other hand, glucose was positively associated with the progression of NAFLD among the female subjects, while levels of threonine were negatively related. Fluctuations in ketone bodies acetoacetate and acetone were also observed among the female subjects probing a significant reduction in the circulatory levels of the former in NAFLD cases. A complex glycine response to hepatic steatosis of the female subjects deserves further investigation. Results of this study aspire to address the paucity of data on sex differences regarding NAFLD pathogenesis. Targeted circulatory metabolome measurements could be used as diagnostic markers for the distinct stages of NAFLD in each sex and eventually aid in the development of novel sex-related therapeutic options.

PREVALENCE OF NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) AMONG CORONARY ARTERY DISEASE PATIENTS AND ITS ASSOCIATION WITH CAD SEVERITY

Background: Non-alcoholic fatty liver disease (NAFLD) is a growing concern due to its potential to lead to liver transplants and its association with cardiovascular disease (CVD). However, the relationship between NAFLD and CVD remains debated, and non-invasive diagnostic methods for NAFLD are recommended. This study aimed to estimate the prevalence of NAFLD among patients with CAD and explore the association between CAD severity and the probability of developing NAFLD.&#x0D; Methodology: A cross-sectional study was conducted among CAD patients. Patients with a history of infectious liver disease, pregnant or lactating individuals, and those with excessive alcohol consumption were excluded. Coronary angiography was performed to assess CAD severity using the Gensini score. Ultrasonography and non-invasive assessments, such as the Fibrosis-4 (FIB-4) index, were used to diagnose and stage NAFLD.&#x0D; Result: The study included 156 CAD patients, with 79 (50.6%) being male. Out of total, 31 (19.8%) had severe, 79(50.6%) had moderate, and 46 (29.48%) had mild NAFLD. Male patients showed a significantly higher prevalence of severe NAFLD compared to females. There was no significant difference in the mean age of CAD patients across NAFLD severities. Severe NAFLD was associated with higher mean Gensini scores and FIB-4 values compared to mild to moderate NAFLD patients. A positive correlation was found between Gensini score and FIB4, suggesting that Gensini score could be an alternative to FIB4 in diagnosing NAFLD severity among CAD patients.&#x0D; Conclusion: The study revealed a high prevalence of NAFLD among CAD patients, with severe NAFLD being associated with higher CAD severity.

Impact of exercise intervention-based remote monitoring for patients with different grades of non-alcoholic fatty liver disease severity

Impact of exercise intervention-based remote monitoring for patients with different grades of non-alcoholic fatty liver disease severity

IL-6 Trans-Signaling Is Increased in Diabetes, Impacted by Glucolipotoxicity, and Associated With Liver Stiffness and Fibrosis in Fatty Liver Disease.

IL-6 and its circulating coreceptor sgp130 are increased in people with fatty liver disease and steatohepatitis. High glucose and lipids stimulated IL-6 and sgp130 secretion from hepatic stellate cells. sgp130 levels correlated with HbA1c, and diabetes concurrent with steatohepatitis further increased circulating levels of all IL-6 trans-signaling mediators. Circulating sgp130 positively correlated with liver stiffness and hepatic fibrosis. Metabolic stress to liver associated with fatty liver disease might shift the balance of IL-6 classical versus trans-signaling, promoting liver fibrosis that is accelerated by diabetes.

A nutrigenetic precision approach for the management of non-alcoholic fatty liver disease

The Patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 single nucleotide polymorphism (SNP) is one of the major genetic determinant of non-alcoholic fatty liver disease (NAFLD) and is strongly regulated by changes in energy balance and dietary factors. We aimed to investigate the association between the PNPLA3 rs738409 SNP, nutrient intake and NAFLD severity. PNPLA3-rs738409 SNP was genotyped in 181 patients with NAFLD who completed the EPIC Food Frequency Questionnaire. Liver steatosis was evaluated by Controlled Attenuation Parameter (CAP) (Fibroscan®530, Echosens). According to the established cut-off, a CAP value≥300dB/m was used to identify severe steatosis (S3). An independent group of 46 biopsy-proven NAFLD subjects was used as validation cohort. Overall, median age was 53 years (range 44; 62) and 60.2% of patients were male. Most subjects (56.3%) had S3 and showed increased liver stiffness (p<0.001), AST (p=0.003) and ALT levels (p<0.001) compared to those with CAP<300dB/m. At logistic regression analyses we found that the interaction between carbohydrates intake and the carriers of the PNPLA3 G risk allele was significantly associated with S3 (p=0.001). The same result was confirmed in the validation cohort, were the interaction between high carbohydrate intake (48%) and PNPLA3 SNP was significantly associated with steatosis ≥33% (p=0.038). The intake of greater than or equal to 48% carbohydrate in NAFLD patients carriers of the CG/GG allele of PNPLA3 rs738409 may increase the risk of significant steatosis.

Lack of associations of microRNAs with severe NAFLD in people living with HIV: discovery case-control study.

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in people living with HIV (PLWH) and the expression of some microRNAs could be useful as biomarkers for the diagnosis of NAFLD. The aim of this study was to identify patterns of differential expression of microRNAs in PLWH and assess their diagnostic value for NALFD. A discovery case-control study with PLWH was carried out. The expression of miRNAs was determined using HTG EdgeSeq technology. Cases were defined as patients with severe NAFLD and controls as patients without NAFLD, characterized using the controlled attenuation parameter (CAP). Cases and controls were matched 1:1 for age, sex, BMI, CD4+ lymphocyte count, active HCV infection, and ART regimen. Serum 2,083 simultaneous microRNA transcripts were analyzed using HTG technology and compared between cases and controls. Forty-five patients, 23 cases, and 22 controls were included in the study. In the analysis of the expression pattern of the 2,083 microRNAs, no differential expression patterns were found between both groups of patients included in the study. Analysis of the microRNA transcriptome profile of nonobese PLWH with severe NAFLD did not appear to differ from that of patients without NAFLD. Thus, microRNA might not serve as a proper biomarker for predicting severe NALFD in this population.