Preserved hemostatic status in patients with non-alcoholic fatty liver disease

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of thrombosis. However, it remains unclear if hypercoagulability contributes to this risk. We, therefore, determined an in-depth hemostatic profile in a cohort of well-defined patients with NAFLD. Methods: We drew blood samples from 68 patients with biopsy proven NAFLD (simple steatosis n = 24, NASH n = 22, and NASH cirrhosis n = 22), 30 lean controls, 30 overweight controls (body mass index (BMI) >25 kg/m(2)), and 15 patients with alcoholic (ASH) cirrhosis, and performed in-depth hemostatic profiling. Results: Basal and agonist-induced platelet activation, plasma levels of markers of platelet activation, and plasma levels of the platelet adhesion regulators von Willebrand factor and ADAMTSI3 were comparable between patients with non cirrhotic NAFLD and controls. Agonist-induced platelet activation was decreased in patients with cirrhosis. Thrombomodulin-modified thrombin generation was comparable between all patients and controls, although patients with cirrhosis had a reduced anticoagulant response to thrombomodulin. Thromboelastography test results were comparable between controls and non-cirrhotic NAFLD patients, but revealed moderate hypocoagulability in cirrhosis. Plasma fibrinolytic potential was decreased in overweight controls and non-cirrhotic NAFLD, but accelerated fibrinolysis was observed in ASH cirrhosis. Clot permeability was decreased in overweight controls and patients with NAFLD. Conclusions: The overall hemostatic profile is comparable between patients with non-cirrhotic NAFLD and controls. Additionally, pro-thrombotic features (hypofibrinolysis and a pro thrombotic structure of fibrin clot) in patients with NAFLD are likely driven by obesity. Our study suggests a limited role for hyperactive hemostasis in the increased thrombotic risk in NAFLD. Lay summary: The combined results of this study show that the overall hemostatic status is comparable between healthy individuals and patients with a fatty liver disease. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved

The transcontinental variability of nonalcoholic fatty liver disease

Aim: To compare the phenotype of lean versus overweight (OW) and obese (OB) subjects with non-alcoholic fatty liver disease (NAFLD) across multiple continents.Methods: A retrospective study of histologically defined subjects from a single center each in France (Fr), Brazil (Br), India (In) and United States (US) was performed.Results: A total of 70 lean [body mass index (BMI) < 25 kg/m2] subjects (Fr:Br:In:US: 16:19:22:13) with NAFLD were compared to 136 OW (BMI > 25 kg/m2, BMI < 29 kg/m2) (n = 28:33:52:23) and 224 OB subjects (BMI > 29 kg/m2) (n = 81:11:22:103). Lean French subjects had the lowest incidence of type 2 diabetes while those from Brazil (P < 0.01) had the highest. Lean subjects had similar low-density lipoprotein-cholesterol, but higher high-density lipoprotein-cholesterol compared to obese subjects in all regions. In both lean and obese subjects, there were both insulin-sensitive and insulin-resistant subjects. Lean French subjects were most insulin-sensitive while those from Brazil were mostly insulin-resistant. For each weight category, subjects from India were more insulin-sensitive than those from other regions. Disease activity increased from lean to overweight to obese in France but was similar across weight categories in other regions.Conclusion: The phenotype of NAFLD in lean subjects varies by region. Some obese subjects with NAFLD are insulin-sensitive. We hypothesize that genetics and region-specific disease modifiers account for these differences

Differential fuel utilization in liver transplant recipients and its relationship with non‐alcoholic fatty liver disease

Metabolic flexibility is the ability to match biofuel availability to utilization. Reduced metabolic flexibility, or lower fatty acid (FA) oxidation in the fasted state, is associated with obesity. The present study evaluated metabolic flexibility after liver transplantation (LT).MethodsPatients receiving LT for non-alcoholic steatohepatitis (NASH) (n = 35) and non-NASH (n = 10) were enrolled. NASH was chosen as these patients are at the highest risk of metabolic complications. Metabolic flexibility was measured using whole-body calorimetry and expressed as respiratory quotient (RQ), which ranges from 0.7 (pure FA oxidation) to 1.0 is (carbohydrate oxidation).ResultsThe two cohorts were similar except for a higher prevalence of obesity and diabetes in the NASH cohort. Post-prandially, RQ increased in both cohorts (i.e. greater carbohydrate utilization) but peak RQ and time at peak RQ was higher in the NASH cohort. Fasting RQ in NASH was significantly higher (0.845 vs. 0.772, p < .001), indicative of impaired FA utilization. In subgroup analysis of the NASH cohort, body mass index but not liver fat content (MRI-PDFF) was an independent predictor of fasting RQ. In NASH, fasting RQ inversely correlated with fat-free muscle volume and directly with visceral adipose tissue.ConclusionReduced metabolic flexibility in patients transplanted for NASH cirrhosis may precede the development of non-alcoholic fatty liver disease after LT

Differential fuel utilization in liver transplant recipients and its relationship with non‐alcoholic fatty liver disease

Metabolic flexibility is the ability to match biofuel availability to utilization. Reduced metabolic flexibility, or lower fatty acid (FA) oxidation in the fasted state, is associated with obesity. The present study evaluated metabolic flexibility after liver transplantation (LT).MethodsPatients receiving LT for non-alcoholic steatohepatitis (NASH) (n = 35) and non-NASH (n = 10) were enrolled. NASH was chosen as these patients are at the highest risk of metabolic complications. Metabolic flexibility was measured using whole-body calorimetry and expressed as respiratory quotient (RQ), which ranges from 0.7 (pure FA oxidation) to 1.0 is (carbohydrate oxidation).ResultsThe two cohorts were similar except for a higher prevalence of obesity and diabetes in the NASH cohort. Post-prandially, RQ increased in both cohorts (i.e. greater carbohydrate utilization) but peak RQ and time at peak RQ was higher in the NASH cohort. Fasting RQ in NASH was significantly higher (0.845 vs. 0.772, p < .001), indicative of impaired FA utilization. In subgroup analysis of the NASH cohort, body mass index but not liver fat content (MRI-PDFF) was an independent predictor of fasting RQ. In NASH, fasting RQ inversely correlated with fat-free muscle volume and directly with visceral adipose tissue.ConclusionReduced metabolic flexibility in patients transplanted for NASH cirrhosis may precede the development of non-alcoholic fatty liver disease after LT

Reduced metabolic flexibility is a predictor of weight gain among liver transplant recipients.

BACKGROUND: Metabolic flexibility is the ability to match biofuel availability to utilization and is inversely associated with increased metabolic burden among liver transplant (LT) recipients. The present study evaluated the impact of metabolic flexibility on weight gain following LT. METHODS: LT recipients were enrolled prospectively (n = 47) and followed for 6 months. Metabolic flexibility was measured using whole room calorimetry and is expressed as respiratory quotient (RQ). Peak RQ represents maximal carbohydrate metabolism and occurs in the post-prandial state, while trough RQ represents maximal fatty acid metabolism occurring in the fasted state. RESULTS: The clinical, metabolic and laboratory characteristics of the study cohort of lost weight (n = 14) and gained weight (n = 33) were similar at baseline. Patients who lost weight were more likely to reach maximal RQ (maximal carbohydrate oxidation) early and rapidly transitioned to trough RQ (maximal fatty acid oxidation). In contrast, patients who gained weight had delayed time to peak RQ and trough RQ. In multivariate modeling, time to peak RQ (β-coefficient 0.509, p = 0.01), time from peak RQ to trough RQ (β-coefficient 0.634, p = 0.006), and interaction between time to peak RQ to trough RQ and fasting RQ (β-coefficient 0.447, p = 0.02) directly correlated with severity of weight gain. No statistically significant relationship between peak RQ, trough RQ and weight change was demonstrated. CONCLUSION: Inefficient transition between biofuels (carbohydrates and fatty acids) is associated with weight gain in LT recipients that is independent of clinical metabolic risk. These data offer novel insight into the physiology of obesity post-LT with potential to develop new diagnostics and therapeutics

Differential fuel utilization in liver transplant recipients and its relationship with non-alcoholic fatty liver disease.

UNLABELLED: Metabolic flexibility is the ability to match biofuel availability to utilization. Reduced metabolic flexibility, or lower fatty acid (FA) oxidation in the fasted state, is associated with obesity. The present study evaluated metabolic flexibility after liver transplantation (LT). METHODS: Patients receiving LT for non-alcoholic steatohepatitis (NASH) (n = 35) and non-NASH (n = 10) were enrolled. NASH was chosen as these patients are at the highest risk of metabolic complications. Metabolic flexibility was measured using whole-body calorimetry and expressed as respiratory quotient (RQ), which ranges from 0.7 (pure FA oxidation) to 1.0 is (carbohydrate oxidation). RESULTS: The two cohorts were similar except for a higher prevalence of obesity and diabetes in the NASH cohort. Post-prandially, RQ increased in both cohorts (i.e. greater carbohydrate utilization) but peak RQ and time at peak RQ was higher in the NASH cohort. Fasting RQ in NASH was significantly higher (0.845 vs. 0.772, p \u3c .001), indicative of impaired FA utilization. In subgroup analysis of the NASH cohort, body mass index but not liver fat content (MRI-PDFF) was an independent predictor of fasting RQ. In NASH, fasting RQ inversely correlated with fat-free muscle volume and directly with visceral adipose tissue. CONCLUSION: Reduced metabolic flexibility in patients transplanted for NASH cirrhosis may precede the development of non-alcoholic fatty liver disease after LT