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A nutrigenetic tool for precision dietary management of non-alcoholic fatty liver disease deeming insulin resistance markers.
Perez-Diaz-Del-Campo, N, Riezu-Boj, JI, Marin-Alejandre, BA, Monreal, JI, Elorz, M, Herrero, JI, Benito-Boillos, A, Milagro, FI, Bugianesi, E, Tur, JA, et al
Panminerva medica. 2022;(4):485-496
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) development is linked to insulin resistance and influenced by environmental factors, but it also underlined a genetic predisposition. The aim of this research was to build a predictive model based on genetic and hepatic health information, deeming insulin resistance markers in order to personalize dietary treatment in overweight/obese subjects with NAFLD. METHODS A 6-month nutritional intervention was conducted in 86 overweight/obese volunteers with NAFLD randomly assigned to 2 energy-restricted diets: the American Heart Association (AHA) diet and the Fatty Liver in Obesity (FLiO) diet. Individuals were genotyped using a predesigned panel of 95 genetic variants. A Genetic Risk Score (GRS) for each diet was computed using statistically relevant SNPs for the change on Fatty Liver Index (FLI) after 6-months of nutritional intervention. Body composition, liver injury and insulin resistance markers, as well as physical activity and dietary intake were also assessed. RESULTS Under energy restriction, both the AHA and FLiO diets induced similar significant improvements on body composition, insulin resistance markers, hepatic health and dietary and lifestyle outcomes. The calculated score included in the linear mixed regression model was able to predict the change of FLI adjusted by diet, age and sex. This model allowed to personalize the most suitable diet for 72% of the volunteers. Similar models were also able to predict the changes on Triglycerides and Glucose (TyG) Index and retinol-binding protein 4 (RBP4) levels depending on diet. CONCLUSIONS Models integrating genetic screening and insulin resistance markers can be useful for the personalization of NAFLD weight loss treatments.
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Transient elastography and serum markers of liver fibrosis associate with epicardial adipose tissue and coronary artery calcium in NAFLD.
Perdomo, CM, Ezponda, A, Núñez-Córdoba, JM, Herrero, JI, Bastarrika, G, Frühbeck, G, Escalada, J
Scientific reports. 2022;(1):6564
Abstract
Non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease morbimortality. However, it is not clear if NAFLD staging may help identify early or subclinical markers of cardiovascular disease. We aimed to evaluate the association of liver stiffness and serum markers of liver fibrosis with epicardial adipose tissue (EAT) and coronary artery calcium (CAC) in an observational cross-sectional study of 49 NAFLD patients that were seen at Clínica Universidad de Navarra (Spain) between 2009 and 2019. Liver elastography and non-invasive fibrosis markers were used to non-invasively measure fibrosis. EAT and CAC, measured through visual assessment, were determined by computed tomography. Liver stiffness showed a direct association with EAT (r = 0.283, p-value = 0.049) and CAC (r = 0.337, p-value = 0.018). NAFLD fibrosis score was associated with EAT (r = 0.329, p-value = 0.021) and CAC (r = 0.387, p-value = 0.006). The association of liver stiffness with CAC remained significant after adjusting for metabolic syndrome features (including carbohydrate intolerance/diabetes, hypertension, dyslipidaemia, visceral adipose tissue, and obesity). The evaluation of NAFLD severity through liver elastography or non-invasive liver fibrosis biomarkers may contribute to guide risk factor modification to reduce cardiovascular risk in asymptomatic patients. Inversely, subclinical cardiovascular disease assessment, through Visual Scale for CAC scoring, may be a simple and effective measure for patients with potential liver fibrosis, independently of the existence of other cardiovascular risk factors.
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Effects of two personalized dietary strategies during a 2-year intervention in subjects with nonalcoholic fatty liver disease: A randomized trial.
Marin-Alejandre, BA, Cantero, I, Perez-Diaz-Del-Campo, N, Monreal, JI, Elorz, M, Herrero, JI, Benito-Boillos, A, Quiroga, J, Martinez-Echeverria, A, Uriz-Otano, JI, et al
Liver international : official journal of the International Association for the Study of the Liver. 2021;(7):1532-1544
Abstract
BACKGROUND AND OBJECTIVES Nonalcoholic fatty liver disease (NAFLD) management is focused on lifestyle modifications, but long-term maintenance is a challenge for many individuals. This study aimed to evaluate the long-term effects of two personalized energy-restricted dietary strategies on weight loss, metabolic and hepatic outcomes in overweight/obese subjects with NAFLD. METHODS Ninety-eight subjects from the Fatty Liver in Obesity (FLiO) study (NCT03183193) were randomly assigned to the American Heart Association (AHA) or the FLiO dietary group in a 2-year controlled trial. Anthropometry, body composition (DXA), biochemical parameters and hepatic status (ultrasonography, Magnetic Resonance Imaging, and elastography) were assessed at baseline, 6, 12 and 24 months. RESULTS Both the AHA and FLiO diets significantly reduced body weight at 6 (-9.7% vs -10.1%), 12 (-6.7% vs -9.6%), and 24 months (-4.8% vs -7.6%) with significant improvements in body composition, biochemical and liver determinations throughout the intervention. At the end of the follow-up, the FLiO group showed a greater decrease in ALT, liver stiffness and Fatty Liver Index, among others, compared to AHA group, although these differences were attenuated when the analyses were adjusted by weight loss percentage. The FLiO group also showed a greater increase in adiponectin compared to AHA group. CONCLUSIONS The AHA and FLiO diets were able to improve body weight and body composition, as well as metabolic and hepatic status of participants with overweight/obesity and NAFLD within a 2-year follow-up. These findings show that both strategies are suitable alternatives for NAFLD management. However, the FLiO strategy may provide more persistent benefits in metabolic and hepatic parameters.
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Ultrasound/Elastography techniques, lipidomic and blood markers compared to Magnetic Resonance Imaging in non-alcoholic fatty liver disease adults.
Cantero, I, Elorz, M, Abete, I, Marin, BA, Herrero, JI, Monreal, JI, Benito, A, Quiroga, J, Martínez, A, Huarte, MP, et al
International journal of medical sciences. 2019;(1):75-83
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) may progress to steatohepatitis, cirrhosis and complicated hepatocellular carcinoma with defined differential symptoms and manifestations. OBJECTIVE To evaluate the fatty liver status by several validated approaches and to compare imaging techniques, lipidomic and routine blood markers with magnetic resonance imaging in adults subjects with non-alcoholic fatty liver disease. MATERIALS AND METHODS A total of 127 overweight/obese with NAFLD, were parallelly assessed by Magnetic Resonance Imaging (MRI), ultrasonography, transient elastography and a validated metabolomic designed test to diagnose NAFLD in this cross-sectional study. Body composition (DXA), hepatic related biochemical measurements as well as the Fatty Liver Index (FLI) were evaluated. This study was registered as FLiO: Fatty Liver in Obesity study; NCT03183193. RESULTS The subjects with more severe liver disease were found to have worse metabolic parameters. Positive associations between MRI with inflammatory and insulin biomarkers were found. A linear regression model including ALT, RBP4 and HOMA-IR was able to explain 40.9% of the variability in fat content by MRI. In ROC analyses a combination panel formed of ALT, HOMA-IR and RBP4 followed by ultrasonography, ALT and metabolomic test showed the major predictive ability (77.3%, 74.6%, 74.3% and 71.1%, respectively) for liver fat content. CONCLUSIONS A panel combination including routine blood markers linked to insulin resistance showed highest associations with MRI considered as a gold standard for determining liver fat content. This combination of tests can facilitate the diagnosis of early stages of non-alcoholic liver disease thereby avoiding other invasive and expensive methods.
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Randomized study showing the benefit of medical study writing multiple choice questions on their learning.
Herrero, JI, Lucena, F, Quiroga, J
BMC medical education. 2019;(1):42
Abstract
BACKGROUND Writing multiple choice questions may be a valuable tool for medical education. We asked medical students to generate multiple choice questions and studied its effect on their exams. We hypothesized that students generating questions would improve their learning. METHODS We randomized students in their second and third years at the School of Medicine to write four multiple choice questions on two different sections of General Pathology (Immunopathology and Electrolyte and acid-base status; second year) and Pathophysiology (Blood and Respiratory system; third year). We analyzed whether students writing questions on a section had better results in the exam test in that section than the rest of the students. RESULTS Seventy-five (38.2%) students wrote questions for General Pathology and 109 (47.6%) for Pathophysiology. Students that wrote questions obtained significantly better results in the exam than those who did not. In General Pathology, students who wrote questions about Immunopathology obtained better results in that section than those who wrote questions about the other section (5.13 versus 3.86 over 10; P = 0.03). In Pathophysiology, the differences between both groups were not significant, but students who wrote good questions about Respiratory system obtained better results in that section than those who wrote good questions about Blood (6.07 versus 4.28 over 10; P = 0.015). Male students wrote good questions in Pathophysiology more frequently than female students (28.1% versus 10.4%; P = 0.02). CONCLUSIONS The writing of multiple choice questions by medical students may improve their learning. A gender effect may also influence this intervention. Future investigations should refine its potential role in teaching.
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Association between Sleep Disturbances and Liver Status in Obese Subjects with Nonalcoholic Fatty Liver Disease: A Comparison with Healthy Controls.
Marin-Alejandre, BA, Abete, I, Cantero, I, Riezu-Boj, JI, Milagro, FI, Monreal, JI, Elorz, M, Herrero, JI, Benito-Boillos, A, Quiroga, J, et al
Nutrients. 2019;11(2)
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Inadequate sleep has been associated with poor health outcomes such as obesity and type 2 diabetes. The relevance of sleep patterns in the onset or progression of non-alcoholic fatty liver disease (NAFLD) is poorly understood. The aim of this cross-sectional study was to investigate the association between sleep characteristics and liver health in obese people with NAFLD compared to normal weight people without NAFLD. 94 overweight or obese patients with NAFLD and 40 normal weight people without NAFLD were enrolled in the study. Measures of liver health such as liver stiffness and levels of liver enzymes were assessed, along with sleep features evaluated using a Sleep Quality Index (SQI). A higher prevalence of short sleep duration and poor sleep quality were found in people with NAFLD. Sleep disturbance or sleep quality predicted up to 20.3% and 20.4% of the variability of liver stiffness, respectively, after adjusting for other factors. The authors of the study suggest that sleep disruption may be contributing to the development of NAFLD, and/or the alteration of the liver may be affecting sleep patterns. Consequently, sleep may be a modifiable behaviour to consider in the prevention and management of NAFLD.
Abstract
The relevance of sleep patterns in the onset or evolution of nonalcoholic fatty liver disease (NAFLD) is still poorly understood. Our aim was to investigate the association between sleep characteristics and hepatic status indicators in obese people with NAFLD compared to normal weight non-NAFLD controls. Ninety-four overweight or obese patients with NAFLD and 40 non-NAFLD normal weight controls assessed by abdominal ultrasonography were enrolled. Hepatic status evaluation considered liver stiffness determined by Acoustic Radiation Force Impulse elastography (ARFI) and transaminases. Additionally, anthropometric measurements, clinical characteristics, and biochemical profiles were determined. Sleep features were evaluated using the Pittsburgh Sleep Quality Index (PSQI). Hepatic status parameters, anthropometric measurements, and clinical and biochemical markers differed significantly in NAFLD subjects compared to controls, as well as sleep efficiency, sleep disturbance score, and sleep quality score. In the NAFLD group, a higher prevalence of short sleep duration (p = 0.005) and poor sleep quality (p = 0.041) were found. Multivariate-adjusted odds ratio (95% confidence interval) for NAFLD considering sleep disturbance was 1.59 (1.11⁻2.28). Regression models that included either sleep disturbance or sleep quality predicted up to 20.3% and 20.4% of the variability of liver stiffness, respectively, and after adjusting for potential confounders. Current findings suggest that sleep disruption may be contributing to the pathogenesis of NAFLD as well as the alteration of the liver may be affecting sleep patterns. Consequently, sleep characteristics may be added to the list of modifiable behaviors to consider in health promotion strategies and in the prevention and management of NAFLD.
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The Metabolic and Hepatic Impact of Two Personalized Dietary Strategies in Subjects with Obesity and Nonalcoholic Fatty Liver Disease: The Fatty Liver in Obesity (FLiO) Randomized Controlled Trial.
Marin-Alejandre, BA, Abete, I, Cantero, I, Monreal, JI, Elorz, M, Herrero, JI, Benito-Boillos, A, Quiroga, J, Martinez-Echeverria, A, Uriz-Otano, JI, et al
Nutrients. 2019;(10)
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. NAFLD management is mainly focused on weight loss, but the optimal characteristics of the diet demand further investigation. This study aims to evaluate the effects of two personalized energy-restricted diets on the liver status in overweight or obese subjects with NAFLD after a 6 months follow-up. Ninety-eight individuals from the Fatty Liver in Obesity (FLiO) study were randomized into two groups and followed different energy-restricted diets. Subjects were evaluated at baseline and after 6 months. Diet, anthropometry, body composition, and biochemical parameters were evaluated. Liver assessment included ultrasonography, Magnetic Resonance Imaging, elastography, and determination of transaminases. Both dietary groups significantly improved their metabolic and hepatic markers after the intervention, with no significant differences between them. Multivariate regression models evidenced a relationship between weight loss, adherence to the Mediterranean Diet (MedDiet), and a decrease in liver fat content, predicting up to 40.9% of its variability after 6 months. Moreover, the antioxidant capacity of the diet was inversely associated with liver fat content. Participants in the group with a higher adherence to the MedDiet showed a greater reduction in body weight, total fat mass, and hepatic fat. These results support the benefit of energy-restricted diets, high adherence to the MedDiet, and high antioxidant capacity of the diet for the management of NAFLD in individuals with overweight or obesity.
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PEG-Interferon-α ribavirin-induced HCV viral clearance: a pharmacogenetic multicenter Spanish study.
Milara, J, Outeda-Macias, M, Aumente-Rubio, MD, Más-Serrano, P, Aldaz, A, Calvo, MV, García-Simón, MS, Martin-Barbero, M, Padullés-Zamora, N, Schoenenberger, JA, et al
Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria. 2015;(1):29-43
Abstract
OBJECTIVE Dual PEGylated interferon-α (PEG-IFN) and ribavirin therapy has been the main hepatitis C virus (HCV) treatment of the last decade. Current direct-acting antiviral agents have improved the outcome of therapy but also have increased the cost and management complexity of treatment. The current study analyzes host genetics, viral and clinical predictors of sustained viral response (SVR) to dual PEG-IFN and ribavirin therapy in a representative Spanish population. METHODS Observational prospective multicentre pharmacogenetic cohort study conducted in 12 different hospitals of 12 different Spanish regions. A total of 98 patients with SVR and 106 with non-SVR in response to PEG-IFN and ribavirin therapy were included. 33 single nucleotide polymorphisms located in 24 different genes related with inflammatory, immune and virus response were selected. Clinical and viral data were also analyzed as candidate of SVR predictors. RESULTS IL-28B (rs12979860, rs7248668, rs8105790, rs8099917) and TNFRSF1B (rs1061622) genotypes, as well as TNFRSF1B/IL-10/TNFα (-308) non-TTG and TNFRSF1B/IL- 10/IL-4 non-TTC haplotypes together with lower age, lower basal HCV RNA load, higher basal serum LDL cholesterol values, VHC genotypes 2 and 3 and basal low grade fibrosis 0-2 were associated with a SVR in the univariate analysis. Independent predictors of SVR in the multivariate analysis were IL-28B rs12979860 CC, TNFRSF1B/IL-10/IL-4 non-TTC along with low baseline HCV RNA load and HCV genotypes 2 and 3. CONCLUSIONS IL-28B rs12979860 CC, TNFRSF1B/ IL-10/ IL-4 non-TTC haplotype, low baseline HCV RNA load and HCV genotypes 2 and 3 may help to predict successful outcome to PEG-IFN/ribavirin therapy in Spanish population.
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Trial of complete weaning from immunosuppression for liver transplant recipients: factors predictive of tolerance.
de la Garza, RG, Sarobe, P, Merino, J, Lasarte, JJ, D'Avola, D, Belsue, V, Delgado, JA, Silva, L, Iñarrairaegui, M, Sangro, B, et al
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2013;(9):937-44
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Abstract
Recipients of liver transplantation (LT) may develop immunological tolerance. Factors predictive of tolerance are not clearly understood. Transplant recipients with normal liver function tests and without active viral hepatitis or autoimmune disease who presented with side effects of immunosuppression or a high risk of de novo malignancies were selected to participate in this prospective study. Twenty-four patients fulfilled the inclusion criteria and, therefore, underwent a gradual reduction of immunosuppression. Tolerance was defined as normal liver function tests after immunosuppression withdrawal. Basal clinical and immunological characteristics, including lymphocyte counts and subpopulations (T, B, natural killer, CD4(+) , CD8(+) , and regulatory T cells) and the phytohemagglutinin stimulation index (SI), were compared for tolerant and nontolerant patients. Fifteen of the 24 patients (62.5%) were tolerant at a median of 14 months (interquartile range = 8.5-22.5 months) after complete immunosuppression withdrawal. Tolerant patients had a longer median interval between transplantation and inclusion in the study (156 for tolerant patients versus 71 months for nontolerant patients, P = 0.003) and a lower median SI (7.49 for tolerant patients versus 41.73 for nontolerant patients, P = 0.01). We identified 3 groups of patients with different probabilities of tolerance: in the first group (n = 7 for an interval > 10 years and an SI < 20), 100% reached tolerance; in the second group (n = 10 for an interval > 10 years and an SI > 20 or an interval < 10 years and an SI < 20), 60% reached tolerance; and in the third group (n = 7 for an interval < 10 years and an SI > 20), 29% reached tolerance. In conclusion, a high proportion of select LT recipients can reach tolerance over the long term. Two simple basal variables-the time from transplantation and the SI-may help to identify these patients.