Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects

<p>Abstract</p> <p>Background</p> <p>CVD in obesity and T2DM are associated with endothelial activation, elevated plasma vascular inflammation markers and a prothrombotic state. We examined the contribution of FFA to these abnormalities following a 48-hour <it>physiological </it>increase in plasma FFA to levels of obesity and diabetes in a group of healthy subjects.</p> <p>Methods</p> <p>40 non-diabetic subjects (age = 38 ± 3 yr, BMI = 28 ± 1 kg/m², FPG = 95 ± 1 mg/dl, HbA_1c= 5.3 ± 0.1%) were admitted twice and received a 48-hour infusion of normal saline or low-dose lipid. Plasma was drawn for intracellular (ICAM-1) and vascular (VCAM-1) adhesion molecules-1, E-selectin (sE-S), myeloperoxidase (MPO) and total plasminogen inhibitor-1 (tPAI-1). Insulin sensitivity was measured by a hyperglycemic clamp (M/I).</p> <p>Results</p> <p>Lipid infusion increased plasma FFA to levels observed in obesity and T2DM and reduced insulin sensitivity by 27% (p = 0.01). Elevated plasma FFA increased plasma markers of endothelial activation ICAM-1 (138 ± 10 vs. 186 ± 25 ng/ml), VCAM-1 (1066 ± 67 vs. 1204 ± 65 ng/ml) and sE-S (20 ± 1 vs. 24 ± 1 ng/ml) between 13-35% and by ≥ 2-fold plasma levels of myeloperoxidase (7.5 ± 0.9 to 15 ± 25 ng/ml), an inflammatory marker of future CVD, and tPAI-1 (9.7 ± 0.6 to 22.5 ± 1.5 ng/ml), an indicator of a prothrombotic state (all p ≤ 0.01). The FFA-induced increase was independent from the degree of adiposity, being of similar magnitude in lean, overweight and obese subjects.</p> <p>Conclusions</p> <p>An increase in plasma FFA within the physiological range observed in obesity and T2DM induces markers of endothelial activation, vascular inflammation and thrombosis in healthy subjects. This suggests that even transient (48-hour) and modest increases in plasma FFA may initiate early vascular abnormalities that promote atherosclerosis and CVD.</p

The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance from the American Association for the Study of Liver Diseases

This guidance provides a data-supported approach to the diagnostic, therapeutic, and preventive aspects of NAFLD care. A “Guidance” document is different from a “Guideline.” Guidelines are developed by a multidisciplinary panel of experts and rate the quality (level) of the evidence and the strength of each recommendation using the Grading of Recommendations, Assessment Development, and Evaluation (GRADE) system. A guidance document is developed by a panel of experts in the topic, and guidance statements, not recommendations, are put forward to help clinicians understand and implement the most recent evidence

A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis

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Greater ectopic fat deposition and liver fibroinflammation, and lower skeletal muscle mass in people with type 2 diabetes

ObjectiveType 2 diabetes (T2D) is associated with significant end-organ damage and ectopic fat accumulation. Multiparametric magnetic resonance imaging (MRI) can provide a rapid, noninvasive assessment of multiorgan and body composition. The primary objective of this study was to investigate differences in visceral adiposity, ectopic fat accumulation, body composition, and relevant biomarkers between people with and without T2D.MethodsParticipant demographics, routine biochemistry, and multiparametric MRI scans of the liver, pancreas, visceral and subcutaneous adipose tissue, and skeletal muscle were analyzed from 266 participants (131 with T2D and 135 without T2D) who were matched for age, gender, and BMI. Wilcoxon and χ2 tests were performed to calculate differences between groups.ResultsParticipants with T2D had significantly elevated liver fat (7.4% vs. 5.3%, p = 0.011) and fibroinflammation (as assessed by corrected T1 [cT1]; 730 milliseconds vs. 709 milliseconds, p = 0.019), despite there being no differences in liver biochemistry, serum aspartate aminotransferase (p = 0.35), or alanine transaminase concentration (p = 0.11). Significantly lower measures of skeletal muscle index (45.2 cm2 /m2 vs. 50.6 cm2 /m2 , p = 0.003) and high-density lipoprotein cholesterol (1.1 mmol/L vs. 1.3 mmol/L, p ConclusionsMultiparametric MRI revealed significantly elevated liver fat and fibroinflammation in participants with T2D, despite normal liver biochemistry. This study corroborates findings of significantly lower measures of skeletal muscle and high-density lipoprotein cholesterol in participants with T2D versus those without T2D

Abdominal obesity and dsyglycemia are risk factors for liver fibrosis progression in NAFLD subjects : A population-based study

To investigate longitudinal changes in the liver stiffness measurement (LSM) in the general adult population without known liver disease and to describe its association with metabolic risk factors, with a special focus on subjects with non-alcoholic fatty liver disease (NAFLD) and dysglycemia. A longitudinal adult population-based cohort study was conducted in Catalonia. LSM was measured by transient elastography (TE) at baseline and follow-up (median: 4.2 years). Subgroup with NAFLD and dysglycemia were analyzed. Moderate-to-advanced liver fibrosis was defined as LSM ≥8.0 kPa and LSM ≥9.2 kPa respectively. Among 1.478 subjects evaluated, the cumulative incidence of LSM ≥8.0 kPa and ≥9.2 kPa at follow-up was 2.8% and 1.9%, respectively. This incidence was higher in NAFLD (7.1% for LSM ≥8.0 kPa and 5% for LSM ≥9.2 kPa) and dysglycemia (6.2% for LSM ≥8.0 kPa and 4.7% for LSM ≥9.2 kPa) subgroups. In the global cohort, the multivariate analyses showed that dysglycemia, abdominal obesity and atherogenic dyslipidemia were significantly associated with progression to moderate-to-advanced liver fibrosis. Female sex was negatively associated. In subjects with NAFLD, abdominal obesity and dysglycemia were associated with changes in LSM to ≥8.0 kPa and ≥9.2 kPa at follow-up. A decline in LSM value to <8 kPa was observed in 64% of those subjects with a baseline LSM ≥8.0 kPa. In this population study, the presence of abdominal obesity and dysglycemia were the main risk metabolic factors associated with moderate-to-advanced liver fibrosis development over time in general populations as well as in subjects with NAFLD

A Reduced Pancreatic Polypeptide Response is Associated With New-onset Pancreatogenic Diabetes Versus Type 2 Diabetes

PURPOSE: Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM). METHODS: Subjects with new-onset DM (\u3c3 \u3eyears\u27 duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of PP concentrations between groups were performed using Wilcoxon rank-sum test and analysis of covariance while adjusting for age, sex, and body mass index. RESULTS: The fasting PP concentration was lower in both the PDAC-DM and CP-DM groups than in the T2DM group (P = 0.03 and CONCLUSIONS: Fasting PP concentrations and the response to meal stimulation are reduced in new-onset DM associated with PDAC or CP compared with T2DM. These findings support further investigations into the use of PP concentrations to characterize pancreatogenic DM and to understand the pathophysiological role in exocrine pancreatic diseases (NCT03460769)

Real-world evidence on non-invasive tests and associated cut-offs used to assess fibrosis in routine clinical practice

Background & Aims: Non-invasive tests (NITs) offer a practical solution for advanced fibrosis identification in non-alcoholic fatty liver disease (NAFLD). Despite increasing implementation, their use is not standardised, which can lead to inconsistent interpretation and risk stratification. We aimed to assess the types of NITs and the corresponding cut-offs used in a range of healthcare settings. Methods: A survey was distributed to a convenience sample of liver health experts who participated in a global NAFLD consensus statement. Respondents provided information on the NITs used in their clinic with the corresponding cut-offs and those used in established care pathways in their areas. Results: There were 35 respondents from 24 countries, 89% of whom practised in tertiary level settings. A total of 14 different NITs were used, and each respondent reported using at least one (median = 3). Of the respondents, 80% reported using FIB-4 and liver stiffness by vibration-controlled transient elastography (Fibroscan®), followed by the NAFLD fibrosis score (49%). For FIB-4, 71% of respondents used a low cut-off of <1.3 (range <1.0 to <1.45) and 21% reported using age-specific cut-offs. For Fibroscan®, 21% of respondents used a single liver stiffness cut-off: 8 kPa in 50%, while the rest used 7.2 kPa, 7.8 kPa and 8.7 kPa. Among the 63% of respondents who used lower and upper liver stiffness cut-offs, there were variations in both values (7.5 to >20 kPa, respectively). Conclusions: The cut-offs used for the same NITs for NAFLD risk stratification vary between clinicians. As cut-offs impact test performance, these findings underscore the heterogeneity in risk-assessment and support the importance of establishing consistent guidelines on the standardised use of NITs in NAFLD management. Lay summary: Owing to the high prevalence of non-alcoholic fatty liver disease (NAFLD) in the general population it is important to identify those who have more advanced stages of liver fibrosis, so that they can be properly treated. Noninvasive tests (NITs) provide a practical way to assess fibrosis risk in patients. However, we found that the cut-offs used for the same NITs vary between clinicians. As cut-offs impact test performance, these findings highlight the importance of establishing consistent guidelines on the standardised use of NITs to optimise clinical management of NAFLD

A global research priority agenda to advance public health responses to fatty liver disease

Background & aims: An estimated 38% of adults worldwide have non-alcoholic fatty liver disease (NAFLD). From individual impacts to widespread public health and economic consequences, the implications of this disease are profound. This study aimed to develop an aligned, prioritised fatty liver disease research agenda for the global health community. Methods: Nine co-chairs drafted initial research priorities, subsequently reviewed by 40 core authors and debated during a threeday in-person meeting. Following a Delphi methodology, over two rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the priorities, via Qualtrics XM, indicating agreement using a four-point Likert-scale and providing written feedback. The core group revised the draft priorities between rounds. In R2, panellists also ranked the priorities within six domains: epidemiology, models of care, treatment and care, education and awareness, patient and community perspectives, and leadership and public health policy. Results: The consensus-built fatty liver disease research agenda encompasses 28 priorities. The mean percentage of ‘agree’ responses increased from 78.3 in R1 to 81.1 in R2. Five priorities received unanimous combined agreement (‘agree’ + ‘somewhat agree’); the remaining 23 priorities had >90% combined agreement. While all but one of the priorities exhibited at least a supermajority of agreement (>66.7% ‘agree’), 13 priorities had 90% combined agreement. Conclusions: Adopting this multidisciplinary consensus-built research priorities agenda can deliver a step-change in addressing fatty liver disease, mitigating against its individual and societal harms and proactively altering its natural history through prevention, identification, treatment, and care. This agenda should catalyse the global health community’s efforts to advance and accelerate responses to this widespread and fast-growing public health threat.Fil: Lazarus, Jeffrey V.. City University of New York; Estados Unidos. Universidad de Barcelona; EspañaFil: Mark, Henry E.. European Association for the Study of the Liver; SuizaFil: Allen, Alina M.. Mayo Clinic; Estados UnidosFil: Arab, Juan Pablo. Pontificia Universidad Católica de Chile; Chile. Western University; CanadáFil: Carrieri, Patrizia. Inserm; Francia. Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale; FranciaFil: Noureddin, Mazen. Houston Methodist Hospital; Estados UnidosFil: Alazawi, William. Queen Mary University of London; Estados UnidosFil: Alkhouri, Naim. Arizona Liver Health; Estados UnidosFil: Alqahtani, Saleh A.. King Faisal Specialist Hospital And Research Centre; Arabia SauditaFil: Arrese, Marco. Universidad Católica de Chile; Chile. Pontificia Universidad Católica de Chile; ChileFil: Bataller, Ramon. Universidad de Barcelona; EspañaFil: Berg, Thomas. Universitat Leipzig; AlemaniaFil: Brennan, Paul N.. University of Dundee; Reino UnidoFil: Burra, Patrizia. Università di Padova; ItaliaFil: Castro Narro, Graciela E.. Instituto Nacional de la Nutrición Salvador Zubiran; México. Fundacion Clinica Medica Sur; México. Asociación Latinoamericana Para El Estudio del Hígado; ChileFil: Cortez Pinto, Helena. Universidade Nova de Lisboa; PortugalFil: Cusi, Kenneth. University of Florida; Estados UnidosFil: Dedes, Nikos. Greek Patients Association; GreciaFil: Duseja, Ajay. Postgraduate Institute of Medical Education and Research; IndiaFil: Francque, Sven M.. Universiteit Antwerp; BélgicaFil: Hagström, Hannes. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Huang, Terry T. K.. City University of New York; Estados UnidosFil: Wajcman, Dana Ivancovsky. Universidad de Barcelona; EspañaFil: Valenti, Luca. Università degli Studi di Milano; ItaliaFil: Zelber-Sagi, Shira. University Of Haifa; Israel. Universitat Tel Aviv; IsraelFil: Schattenberg, Jörn M.. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Wong, Vincent Wai-Sun. Chinese University Of Hong Kong; Hong KongFil: Younossi, Zobair M.. Universiteit Antwerp; BélgicaFil: Zheng, Kenneth I.. Universiteit Antwerp; BélgicaFil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Universidad Abierta Interamericana; Argentin