Aspirin for Metabolic Dysfunction-Associated Steatotic Liver Disease Without Cirrhosis: A Randomized Clinical Trial.

Importance: Aspirin may reduce severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown. Objective: To test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD. Design, Setting, and Participants: This 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023. Interventions: Participants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months. Main Outcomes and Measures: The primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified. Results: Among 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was -6.6% with aspirin vs 3.6% with placebo (difference, -10.2% [95% CI, -27.7% to -2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (-8.8 vs 30.0 percentage points; mean difference, -38.8 percentage points [95% CI, -66.7 to -10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (-2.7% vs 0.9%; mean difference, -3.7% [95% CI, -6.1% to -1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (-11.7 vs 15.7 percentage points; mean difference, -27.3 percentage points [95% CI, -45.2 to -9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn. Conclusions and Relevance: In this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04031729.

Prevalence of steatotic liver disease, MASLD, MetALD and significant fibrosis in people with HIV in the United States.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been proposed as a replacement term for NAFLD. AIMS: To assess the effects of this new nomenclature on the prevalence and distribution of different SLD categories in people with HIV (PWH) and identified factors associated with MASLD and clinically significant fibrosis (CSF). METHODS: PWH were prospectively enrolled from 9 US centres and underwent clinical evaluation and vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). SLD was defined as CAP ≥ 263 dB/m, CSF as LSM of ≥8 kPa, and advanced fibrosis (AF) as LSM ≥ 12 kPa. The prevalence of SLD, MASLD, metabolic dysfunction and alcohol-associated liver disease (MetALD), ALD, cryptogenic (cSLD), CSF and AF were determined. Uni- and multivariate logistic regression models were used to assess factors associated with MASLD and CSF risk. RESULTS: Of 1065 participants, 74% were male, mean (SD) age 51.6 ± 11.9 years, 46% non-Hispanic Black and 74% with undetectable HIV RNA. The prevalence of SLD was 52%, MASLD 39%, MetALD 10%, ALD 3%, CSF 15% and AF 4%. Only 0.6% had cSLD. Black race was protective whereas obesity, ALT and AST levels were associated with increased risk of MASLD and CSF in MASLD. HIV or antiretroviral therapy did not affect MASLD risk. CONCLUSIONS: MASLD and MetALD are the dominant causes of SLD in PWH, affecting almost half. Application of the new nomenclature resulted in minimal change in the proportion of patients with MASLD who would have been diagnosed previously with NAFLD.

ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits.

Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductive stress is sufficient to activate the transcription factor ChREBP and necessary for its activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepatic reductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerol species, which are also influenced by ChREBP. We define the transcriptional signature of hepatic reductive stress and show its upregulation in fatty liver disease and downregulation after bariatric surgery in humans. These findings highlight how a GCKR-reductive stress-ChREBP axis influences multiple human metabolic traits.

Effect of combined tobacco use and type 2 diabetes mellitus on prevalent fibrosis in patients with MASLD.

BACKGROUND: Several studies have investigated the independent effect of cigarette smoking or type 2 diabetes mellitus (T2DM) on MASLD. However, the interaction effect between tobacco consumption and T2DM on MASLD severity remains underexplored. In this study, we assessed the combined effect of tobacco use and T2DM on hepatic fibrosis in MASLD. METHODS: We conducted a single-center retrospective cross-sectional analysis of eligible participants from the Mass General Brigham Fibroscan© database. The participants were divided into 3 groups: those with T2DM and a history of tobacco use (primary exposure group), those with T2DM but no history of tobacco use (secondary exposure group), and those without T2DM and no history of tobacco use (reference group). An additional model was developed, which included a fourth group, participants with a history of tobacco use but no T2DM. The likelihood of fibrosis was determined using a defined fibrosis-4 index cutoff value of 1.3. In addition, we computed the estimated marginal means for liver stiffness measurement and compared the values among the exposure groups. Bivariable and multivariable logistic regression models were used to explore the associations between the exposure groups and the risk for hepatic fibrosis. RESULTS: Overall, 598 individuals were enrolled in the study. The bivariable logistic regression model revealed a significant independent association between T2DM, combined smoking and T2DM, and the outcome of interest, fibrosis. Age, sex, metabolic syndrome, aspirin use, statin use, hemoglobin A1C (A1C), and total bilirubin level were also significantly associated with fibrosis. In the adjusted fibrosis-4 multivariable model (comparing exposure groups to controls), cigarette smoking and T2DM interaction had higher odds of prevalent fibrosis (aOR, 3.04; 95% CI, 1.62-5.76), compared to those with T2DM alone (aOR 2.28; 95% CI, 1.37-3.85). The continuous liver stiffness measurement comparison across the exposure group showed an estimated marginal means of 6.26 (95% CL: 5.58-6.94), 7.54 (95% CL: 6.78-8.30), and 7.88 (6.78-8.99) for the reference group, T2DM only group, and tobacco-T2DM group, respectively. The diabetes-only group and the combined tobacco-T2DM group had statistically significant associations with liver stiffness measurement (p values: 0.013 and 0.014, respectively). CONCLUSION: Although diabetes is independently associated with hepatic fibrosis in patients with MASLD, the combination of tobacco consumption and diabetes is associated with a higher prevalence of fibrosis. Therefore, lifestyle change through tobacco use cessation in patients with diabetes could be beneficial in reducing the incidence of liver fibrosis among individuals with MASLD.

CT Texture Analysis in Nonalcoholic Fatty Liver Disease (NAFLD).

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease worldwide. There are limited biomarkers that can detect progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The purpose of our study was to utilize CT texture analysis to distinguish steatosis from NASH. Methods: 16 patients with NAFLD (38% male, median (interquartile range): age 57 (48-64) years, BMI 37.5 (35.0-46.8) kg/m2) underwent liver biopsy and abdominal non-contrast CT. CT texture analysis was performed to quantify gray-level tissue summaries (e.g., entropy, kurtosis, skewness, and attenuation) using commercially available software (TexRad, Cambridge England). Logistic regression analyses were performed to quantify the association between steatosis/NASH status and CT texture. ROC curve analysis was performed to determine sensitivity, specificity, AUC, 95% CIs, and cutoff values of texture parameters to differentiate steatosis from NASH. Results: By histology, 6/16 (37%) of patients had simple steatosis and 10/16 (63%) had NASH. Patients with NASH had lower entropy (median, interquartile range (IQR): 4.3 (4.1, 4.8) vs. 5.0 (4.9, 5.2), P = 0.013) and lower mean value of positive pixels (MPP) (34.4 (21.8, 52.2) vs. 66.5 (57.0, 70.7), P = 0.009) than those with simple steatosis. Entropy values below 4.73 predict NASH with 100% (95%CI: 67-100%) specificity and 80% (50-100%) sensitivity, AUC: 0.88. MPP values below 54.0 predict NASH with 100% (67-100%) specificity and 100% (50-100%) sensitivity, AUC 0.90. Conclusion: Our study provides preliminary evidence that CT texture analysis may serve as a novel imaging biomarker for disease activity in NAFLD and the discrimination of steatosis and NASH.

Growth Hormone Administration Improves Nonalcoholic Fatty Liver Disease in Overweight/Obesity: A Randomized Trial.

CONTEXT: Overweight and obesity are associated with relative growth hormone (GH) deficiency, which has been implicated in the development of nonalcoholic fatty liver disease (NAFLD). NAFLD is a progressive disease without effective treatments. OBJECTIVE: We hypothesized that GH administration would reduce hepatic steatosis in individuals with overweight/obesity and NAFLD. METHODS: In this 6-month randomized, double-blind, placebo-controlled trial of low-dose GH administration, 53 adults aged 18 to 65 years with BMI ≥25 kg/m2 and NAFLD without diabetes were randomized to daily subcutaneous GH or placebo, targeting insulin-like growth factor 1 (IGF-1) to the upper normal quartile. The primary endpoint was intrahepatic lipid content (IHL) by proton magnetic resonance spectroscopy (1H-MRS) assessed before treatment and at 6 months. RESULTS: Subjects were randomly assigned to a treatment group (27 GH; 26 placebo), with 41 completers (20 GH and 21 placebo) at 6 months. Reduction in absolute % IHL by 1H-MRS was significantly greater in the GH vs placebo group (mean ± SD: -5.2 ± 10.5% vs 3.8 ± 6.9%; P = .009), resulting in a net mean treatment effect of -8.9% (95% CI, -14.5 to -3.3%). All side effects were similar between groups, except for non-clinically significant lower extremity edema, which was more frequent in the GH vs placebo group (21% vs 0%, P = .02). There were no study discontinuations due to worsening of glycemic status, and there were no significant differences in change in glycemic measures or insulin resistance between the GH and placebo groups. CONCLUSION: GH administration reduces hepatic steatosis in adults with overweight/obesity and NAFLD without worsening glycemic measures. The GH/IGF-1 axis may lead to future therapeutic targets for NAFLD.

Physical Activity and Nonalcoholic Fatty Liver Disease: A Roundtable Statement from the American College of Sports Medicine.

ABSTRACT: Although physical activity (PA) is crucial in the prevention and clinical management of nonalcoholic fatty liver disease, most individuals with this chronic disease are inactive and do not achieve recommended amounts of PA. There is a robust and consistent body of evidence highlighting the benefit of participating in regular PA, including a reduction in liver fat and improvement in body composition, cardiorespiratory fitness, vascular biology, and health-related quality of life. Importantly, the benefits of regular PA can be seen without clinically significant weight loss. At least 150 min of moderate or 75 min of vigorous intensity PA are recommended weekly for all patients with nonalcoholic fatty liver disease, including those with compensated cirrhosis. If a formal exercise training program is prescribed, aerobic exercise with the addition of resistance training is preferred. In this roundtable document, the benefits of PA are discussed, along with recommendations for 1) PA assessment and screening; 2) how best to advise, counsel, and prescribe regular PA; and 3) when to refer to an exercise specialist.

American College of Sports Medicine (ACSM) International Multidisciplinary Roundtable report on physical activity and nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: We present findings from the inaugural American College of Sports Medicine (ACSM) International Multidisciplinary Roundtable, which was convened to evaluate the evidence for physical activity as a means of preventing or modifying the course of NAFLD. APPROACH AND RESULTS: A scoping review was conducted to map the scientific literature and identify key concepts, research gaps, and evidence available to inform clinical practice, policymaking, and research. The scientific evidence demonstrated regular physical activity is associated with decreased risk of NAFLD development. Low physical activity is associated with a greater risk for disease progression and extrahepatic cancer. During routine health care visits, all patients with NAFLD should be screened for and counseled about physical activity benefits, including reduction in liver fat and improvement in body composition, fitness, and quality of life. While most physical activity benefits occur without clinically significant weight loss, evidence remains limited regarding the association between physical activity and liver fibrosis. At least 150 min/wk of moderate or 75 min/wk of vigorous-intensity physical activity are recommended for all patients with NAFLD. If a formal exercise training program is prescribed, aerobic exercise with the addition of resistance training is preferred. CONCLUSIONS: The panel found consistent and compelling evidence that regular physical activity plays an important role in preventing NAFLD and improving intermediate clinical outcomes. Health care, fitness, and public health professionals are strongly encouraged to disseminate the information in this report. Future research should prioritize determining optimal strategies for promoting physical activity among individuals at risk and in those already diagnosed with NAFLD.

Resection of NAFLD/NASH-related Hepatocellular Carcinoma (HCC): Clinical Features and Outcomes Compared with HCC Due to Other Etiologies.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are the leading causes of hepatocellular carcinoma (HCC) worldwide. Limited data exist on surgical outcomes for NAFLD/NASH-related HCC compared with other HCC etiologies. We evaluated differences in clinicopathological characteristics and outcomes of patients undergoing surgical resection for NAFLD/NASH-associated HCC compared with other HCC etiologies. METHODS: Demographic, clinicopathological features, and survival outcomes of patients with surgically resected HCC were collected. NAFLD activity score (NAS) and fibrosis score were assessed by focused pathologic review in a subset of patients. RESULTS: Among 492 patients screened, 260 met eligibility (NAFLD/NASH [n = 110], and other etiologies [n = 150]). Median age at diagnosis was higher in the NAFLD/NASH HCC cohort compared with the other etiologies cohort (66.7 vs. 63.4 years, respectively, P = .005), with an increased percentage of female patients (36% vs. 18%, P = .001). NAFLD/NASH-related tumors were more commonly >5 cm (66.0% vs. 45%, P = .001). There were no significant differences in rates of lymphovascular or perineural invasion, histologic grade, or serum AFP levels. The NAFLD/NASH cohort had lower rates of background liver fibrosis, lower AST and ALT levels, and higher platelet counts (P < .01 for all). Median overall survival (OS) was numerically shorter in NAFLD/NASH vs other etiology groups, however, not statistically significant. CONCLUSIONS: Patients with NAFLD/NASH-related HCC more commonly lacked liver fibrosis and presented with larger HCCs compared with patients with HCC from other etiologies. No differences were seen in rates of other high-risk features or survival. With the caveat of sample size and retrospective analysis, this supports a similar decision-making approach regarding surgical resection for NAFLD/NASH and other etiology-related HCCs.

Non-alcoholic fatty liver disease is not associated with impairment in health-related quality of life in virally suppressed persons with human immune deficiency virus.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in persons with HIV (PWH) (HIV-NAFLD). It is unknown if HIV-NAFLD is associated with impairment in health-related quality of life (HRQOL). We examined HRQOL in PWH with and without NAFLD, compared HRQOL in HIV- versus primary NAFLD, and determined factors associated with HRQOL in these groups. Prospectively enrolled 200 PWH and 474 participants with primary NAFLD completed the Rand SF-36 assessment which measures 8 domains of HRQOL. Individual domain scores were used to create composite physical and mental component summary scores. Univariate and multivariate analyses determined variables associated with HRQOL in PWH and in HIV- and primary NAFLD. In PWH, 48% had HIV-NAFLD, 10.2% had clinically significant fibrosis, 99.5% were on antiretroviral therapy, and 96.5% had HIV RNA <200 copies/ml. There was no difference in HRQOL in PWH with or without NAFLD. Diabetes, non-Hispanic ethnicity, and nadir CD4 counts were independently associated with impaired HRQOL in PWH. In HIV-NAFLD, HRQOL did not differ between participants with or without clinically significant fibrosis. Participants with HIV-NAFLD compared to those with primary NAFLD were less frequently cisgender females, White, more frequently Hispanic, had lower BMI and lower frequency of obesity and diabetes. HRQOL of individuals with HIV-NAFLD was not significantly different from those with primary NAFLD. In conclusion, in virally suppressed PWH, HRQOL is not different between participants with or without HIV-NAFLD. HRQOL is not different between HIV-NAFLD and primary NAFLD.

Burden of fatty liver and hepatic fibrosis in persons with HIV: A diverse cross-sectional US multicenter study.

BACKGROUND AIMS: The current prevalence of fatty liver disease (FLD) due to alcohol-associated (AFLD) and nonalcoholic (NAFLD) origins in US persons with HIV (PWH) is not well defined. We prospectively evaluated the burden of FLD and hepatic fibrosis in a diverse cohort of PWH. APPROACH RESULTS: Consenting participants in outpatient HIV clinics in 3 centers in the US underwent detailed phenotyping, including liver ultrasound and vibration-controlled transient elastography for controlled attenuation parameter and liver stiffness measurement. The prevalence of AFLD, NAFLD, and clinically significant and advanced fibrosis was determined. Univariate and multivariate logistic regression models were used to evaluate factors associated with the risk of NAFLD. Of 342 participants, 95.6% were on antiretroviral therapy, 93.9% had adequate viral suppression, 48.7% (95% CI 43%-54%) had steatosis by ultrasound, and 50.6% (95% CI 45%-56%) had steatosis by controlled attenuation parameter ≥263 dB/m. NAFLD accounted for 90% of FLD. In multivariable analysis, old age, higher body mass index, diabetes, and higher alanine aminotransferase, but not antiretroviral therapy or CD4 + cell count, were independently associated with increased NAFLD risk. In all PWH with fatty liver, the frequency of liver stiffness measurement 8-12 kPa was 13.9% (95% CI 9%-20%) and ≥12 kPa 6.4% (95% CI 3%-11%), with a similar frequency of these liver stiffness measurement cutoffs in NAFLD. CONCLUSIONS: Nearly half of the virally-suppressed PWH have FLD, 90% of which is due to NAFLD. A fifth of the PWH with FLD has clinically significant fibrosis, and 6% have advanced fibrosis. These data lend support to systematic screening for high-risk NAFLD in PWH.

Proteomic Analysis of Hepatic Fibrosis in Human Immunodeficiency Virus-Associated Nonalcoholic Fatty Liver Disease Demonstrates Up-regulation of Immune Response and Tissue Repair Pathways.

BACKGROUND: Human immunodeficiency virus (HIV)-associated nonalcoholic fatty liver disease (NAFLD) is characterized by a high prevalence of hepatic fibrosis as a strong clinical predictor of all-cause and liver-specific mortality risk. METHODS: We leveraged data from an earlier clinical trial to define the circulating proteomic signature of hepatic fibrosis in HIV-associated NAFLD. A total of 183 plasma proteins within 2 high-multiplex panels were quantified at baseline and at 12 months (Olink Cardiovascular III; Immuno-Oncology). RESULTS: Twenty proteins were up-regulated at baseline among participants with fibrosis stages 2-3 versus 0-1. Proteins most differentially expressed included matrix metalloproteinase 2 (P < .001), insulin-like growth factor-binding protein 7 (P = .001), and collagen α1(I) chain (P = .001). Proteins were enriched within pathways including response to tumor necrosis factor and aminopeptidase activity. Key proteins correlated directly with visceral adiposity and glucose intolerance and inversely with CD4+ T-cell count. Within the placebo-treated arm, 11 proteins differentially increased among individuals with hepatic fibrosis progression over a 12-month period (P < .05). CONCLUSIONS: Among individuals with HIV-associated NAFLD, hepatic fibrosis was associated with a distinct proteomic signature involving up-regulation of tissue repair and immune response pathways. These findings enhance our understanding of potential mechanisms and biomarkers of hepatic fibrosis in HIV.

NAFLD in Cardiovascular Diseases: A Contributor or Comorbidity?

Nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases are both highly prevalent conditions around the world, and emerging data have shown an association between them. This review found several longitudinal and cross-sectional studies showing that NAFLD was associated with coronary artery disease, cardiac remodeling, aortic valve remodeling, mitral annulus valve calcifications, diabetic cardiomyopathy, diastolic cardiac dysfunction, arrhythmias, and stroke. Although the specific underlying mechanisms are not clear, many hypotheses have been suggested, including that metabolic syndrome might act as an upstream metabolic defect, leading to end-organ manifestations in both the heart and liver. Management of NAFLD includes weight loss through lifestyle interventions or bariatric surgery, and pharmacological interventions, often targeting comorbidities. Although there are no Food and Drug Administration-approved nonalcoholic steatohepatitis-specific therapies, several drug candidates have demonstrated effect in the improvement in fibrosis or nonalcoholic steatohepatitis resolution. Further studies are needed to assess the effect of those interventions on cardiovascular outcomes, the major cause of mortality in patients with NAFLD. In conclusion, a more comprehensive, multidisciplinary approach to diagnosis and management of patients with NAFLD and cardiovascular diseases is needed to optimize clinical outcomes.

Risk factors for cardiovascular disease among individuals with hepatic steatosis.

Cardiovascular disease (CVD) is the leading cause of mortality in adults with hepatic steatosis (HS). However, risk factors for CVD in HS are unknown. We aimed to identify factors associated with coronary artery disease (CAD) and incident major adverse cardiovascular events (MACE) in individuals with HS. We performed a nested cohort study of adults with HS detected on coronary computed tomography in the PROspective Multicenter Imaging Study for Evaluation of chest pain (PROMISE) trial. Obstructive CAD was defined as ≥50% coronary stenosis. MACE included hospitalization for unstable angina, nonfatal myocardial infarction, or all-cause death. Multivariate modeling, adjusted for age, sex, atherosclerotic CVD (ASCVD) risk score and body mass index, identified factors associated with obstructive CAD. Cox regression, adjusted for ASCVD risk score, determined the predictors of MACE. A total of 959 of 3,756 (mean age 59.4 years, 55.0% men) had HS. Obstructive CAD was present in 15.2% (145 of 959). Male sex (adjusted odds ratio [aOR] = 1.83, 95% confidence interval [CI] 1.18-1.2.84; p = 0.007), ASCVD risk score (aOR = 1.05, 95% CI 1.03-1.07; p < 0.001), and n-terminal pro-b-type natriuretic peptide (NT-proBNP; aOR = 1.90, 95% CI 1.38-2.62; p < 0.001) were independently associated with obstructive CAD. In the 25-months median follow-up, MACE occurred in 4.4% (42 of 959). Sedentary lifestyle (adjusted hazard ratio [aHR] = 2.53, 95% CI 1.27-5.03; p = 0.008) and NT-proBNP (aOR = 1.50, 95% CI 1.01-2.25; p = 0.046) independently predicted MACE. Furthermore, the risk of MACE increased by 3% for every 1% increase in ASCVD risk score (aHR = 1.03, 95% CI 1.01-1.05; p = 0.02). Conclusion: In individuals with HS, male sex, NT-pro-BNP, and ASCVD risk score are associated with obstructive CAD. Furthermore, ASCVD, NT-proBNP, and sedentary lifestyle are independent predictors of MACE. These factors, with further validation, may help risk-stratify adults with HS for incident CAD and MACE.

Visualizing biomarkers and their association with clinical outcomes: A machine learning approach.

INTRODUCTION: Clinical investigators often seek to identify biomarkers that are associated with clinical outcomes. The challenge is that biomarkers tend to be numerous, often inter-correlated, and with varying degrees of association with the clinical outcome of interest. We developed a straightforward, effective visualization approach that allows investigators to see the inter-correlations of biomarkers and their association with clinical outcomes rendered in a 2-dimensional (2-D) plot. METHOD: We extracted pairwise differences between outcome groups. Next, a t-SNE machine learning method was applied to reduce dimensionality of the data into 2-dimensional data. This data was then rendered as 2-D plots allowing visualization of either the original biomarker values or their ranking in the sample. We apply this method to a dataset of 235 subjects with data of 114 metabolomic biomarkers and cardiovascular outcomes. RESULT: The 2-D plots demonstrated that the metabolite biomarkers with high degrees of association with the outcome tend to be positioned away from non-significant markers. Markers that are correlated with each other are positioned in clusters. An online demo version application of this visualization tool is available at http://52.9.140.88:3838/MarkersVu/. CONCLUSION: This is an effective approach to visualize biomarkers and their correlations, allowing rapid visual identification of biomarkers and marker clusters with potentially higher degree of association with the outcome.

Analysis of a Simulation Model to Estimate Long-term Outcomes in Patients with Nonalcoholic Fatty Liver Disease.

Importance: Quantitative assessment of disease progression in patients with nonalcoholic fatty liver disease (NAFLD) has not been systematically examined using competing liver-related and non-liver-related mortality. Objective: To estimate long-term outcomes in NAFLD, accounting for competing liver-related and non-liver-related mortality associated with the different fibrosis stages of NAFLD using a simulated patient population. Design, Setting, and Participants: This decision analytical modeling study used individual-level state-transition simulation analysis and was conducted from September 1, 2017, to September 1, 2021. A publicly available interactive tool, dubbed NAFLD Simulator, was developed that simulates the natural history of NAFLD by age and fibrosis stage at the time of (hypothetical) diagnosis defined by liver biopsy. Model health states were defined by fibrosis states F0 to F4, decompensated cirrhosis, hepatocellular carcinoma (HCC), and liver transplant. Simulated patients could experience nonalcoholic steatohepatitis resolution, and their fibrosis stage could progress or regress. Transition probabilities between states were estimated from the literature as well as calibration, and the model reproduced the outcomes of a large observational study. Exposure: Simulated natural history of NAFLD. Main Outcomes and Measures: Main outcomes were life expectancy; all cause, liver-related, and non-liver-related mortality; and cumulative incidence of decompensated cirrhosis and/or HCC. Results: The model included 1 000 000 simulated patients with a mean (range) age of 49 (18-75) years at baseline, including 66% women. The life expectancy of patients aged 49 years was 25.3 (95% CI, 20.1-29.8) years for those with F0, 25.1 (95% CI, 20.1-29.4) years for those with F1, 23.6 (95% CI, 18.3-28.2) years for those with F2, 21.1 (95% CI, 15.6-26.3) years for those with F3, and 13.8 (95% CI, 10.3-17.6) years for those with F4 at the time of diagnosis. The estimated 10-year liver-related mortality was 0.1% (95% uncertainty interval [UI], <0.1%-0.2%) in F0, 0.2% (95% UI, 0.1%-0.4%) in F1, 1.0% (95% UI, 0.6%-1.7%) in F2, 4.0% (95% UI, 2.5%-5.9%) in F3, and 29.3% (95% UI, 21.8%-35.9%) in F4. The corresponding 10-year non-liver-related mortality was 1.8% (95% UI, 0.6%-5.0%) in F0, 2.4% (95% UI, 0.8%-6.3%) in F1, 5.2% (95% UI, 2.0%-11.9%) in F2, 9.7% (95% UI, 4.3%-18.1%) in F3, and 15.6% (95% UI, 10.1%-21.7%) in F4. Among patients aged 65 years, estimated 10-year non-liver-related mortality was higher than liver-related mortality in all fibrosis stages (eg, F2: 16.7% vs 0.8%; F3: 28.8% vs 3.0%; F4: 40.8% vs 21.9%). Conclusions and Relevance: This decision analytic model study simulated stage-specific long-term outcomes, including liver- and non-liver-related mortality in patients with NAFLD. Depending on age and fibrosis stage, non-liver-related mortality was higher than liver-related mortality in patients with NAFLD. By translating surrogate markers into clinical outcomes, the NAFLD Simulator could be used as an educational tool among patients and clinicians to increase awareness of the health consequences of NAFLD.

Expression of IGF-1 receptor and GH receptor in hepatic tissue of patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

OBJECTIVE: The GH and IGF-1 axis is a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) given its lipolytic, anti-inflammatory and anti-fibrotic properties. IGF-1 receptor (IGF-1R) and GH receptor (GHR) expression in adult, human hepatic tissue is not well understood across the spectrum of NAFLD severity. Therefore, we sought to investigate hepatic IGF-1R and GHR expression in subjects with NAFLD utilizing gene expression analysis (GEA) and immunohistochemistry (IHC). DESIGN: GEA (n = 318) and IHC (n = 30) cohorts were identified from the Massachusetts General Hospital NAFLD Tissue Repository. GEA subjects were categorized based on histopathology as normal liver histology (NLH), steatosis only (Steatosis), nonalcoholic steatohepatitis (NASH) without fibrosis (NASH F0), and NASH with fibrosis (NASH F1-4) with GEA by the Nanostring nCounter assay. IHC subjects were matched for age, body mass index (BMI), sex, and diabetic status across three groups (n = 10 each): NLH, Steatosis, and NASH with fibrosis (NASH F1-3). IHC for IGF-1R, IGF-1 and GHR was performed on formalin-fixed, paraffin-embedded hepatic tissue samples. RESULTS: IGF-1R gene expression did not differ across NAFLD severity while IGF-1 gene expression decreased with increasing NAFLD severity, including when controlled for BMI and age. GHR expression did not differ by severity of NAFLD based on GEA or IHC. CONCLUSIONS: IGF-1R and GHR expression levels were not significantly different across NAFLD disease severity. However, expression of IGF-1 was lower with increasing severity of NAFLD. Additional research is needed regarding the contribution of the GH/IGF-1 axis to the pathophysiology of NAFLD and NASH.

The GH/IGF-1 Axis Is Associated With Intrahepatic Lipid Content and Hepatocellular Damage in Overweight/Obesity.

CONTEXT: Obesity is a state of relative growth hormone (GH) deficiency, and GH has been identified as a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) because of its lipolytic and anti-inflammatory properties. However, the GH/IGF-1 axis has not been well characterized in NAFLD. OBJECTIVE: We aimed to investigate serum GH and IGF-1 levels in relation to intrahepatic lipid content (IHL) and markers of hepatocellular damage and fibrosis in NAFLD. METHODS: This cross-sectional study included 102 adults (43% women; age 19-67; BMI ≥ 25 kg/m2) without type 2 diabetes. IHL was measured by magnetic resonance spectroscopy; NAFLD was defined by ≥ 5% IHL. Peak-stimulated GH in response to GH releasing hormone and arginine was assessed as was serum IGF-1 (LC/MS). RESULTS: There was no difference in mean age, BMI, or sex distribution in NAFLD vs controls. Mean (± SD) IHL was higher in NAFLD vs controls (21.8 ±â€…13.3% vs 2.9 ±â€…1.1%, P < 0.0001). Mean peak-stimulated GH was lower in NAFLD vs controls (9.0 ±â€…6.3 vs 15.4 ±â€…11.2 ng/mL, P = 0.003), including after controlling for age, sex, visceral adipose tissue, and fasting glucose. In a stepwise model, peak-stimulated GH predicted 14.6% of the variability in IHL (P = 0.004). Higher peak-stimulated GH was also associated with lower ALT. Higher serum IGF-1 levels were associated with lower risk of liver fibrosis by Fibrosis-4 scores. CONCLUSION: Individuals with NAFLD have lower peak-stimulated GH levels but similar IGF-1 levels as compared to controls. Higher peak-stimulated GH levels are associated with lower IHL and less hepatocellular damage. Higher IGF-1 levels are associated with more favorable fibrosis risk scores. These data implicate GH and IGF-1 as potential disease modifiers in the development and progression of NAFLD.

Atorvastatin favorably modulates a clinical hepatocellular carcinoma risk gene signature.

Lipophilic but not hydrophilic statins have been shown to be associated with reduced risk for hepatocellular carcinoma (HCC) in patients with chronic viral hepatitis. We investigated differential actions of lipophilic and hydrophilic statins and their ability to modulate a clinical prognostic liver signature (PLS) predicting HCC risk in patients with liver disease. Hepatitis C virus (HCV)-infected Huh7.5.1 cells, recently developed as a model to screen HCC chemopreventive agents, were treated with lipophilic statins (atorvastatin and simvastatin) and hydrophilic statins (rosuvastatin and pravastatin), and then analyzed by RNA sequencing and PLS. Lipophilic statins, particularly atorvastatin, more significantly suppressed the HCV-induced high-risk pattern of PLS and genes in YAP and AKT pathway implicated in fibrogenesis and carcinogenesis, compared with the hydrophilic statins. While atorvastatin inhibited YAP activation through the mevalonate pathway, the distinctive AKT inhibition of atorvastatin was mediated by stabilizing truncated retinoid X receptor alpha, which has been known to enhance AKT activation, representing a target for HCC chemoprevention. In addition, atorvastatin modulated the high-risk PLS in an in vitro model of nonalcoholic fatty liver disease (NAFLD). Conclusion: Atorvastatin distinctively inhibits YAP and AKT activation, which are biologically implicated in HCC development, and attenuates a high-risk PLS in an in vitro model of HCV infection and NAFLD. These findings suggest that atorvastatin is the most potent statin to reduce HCC risk in patients with viral and metabolic liver diseases.

Intermittent Fasting as a Treatment for Nonalcoholic Fatty Liver Disease: What Is the Evidence?

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