The biochemical pattern defines MASLD phenotypes linked to distinct histology and prognosis.

BACKGROUND: MASLD can manifest as hepatocellular damage, which can result in mild elevation of aminotransferases. However, in some patients, MASLD presents with cholestatic pattern. OBJECTIVE: To assess the impact of the biochemical pattern on the natural course of MASLD, including liver damage in histology, the accuracy of non-invasive tests(NITs), and prognosis. METHODS: Multicenter study enrolling 2156 patients with biopsy-proven MASLD, who were classified based on their[ALT/ULN)]/[(ALP/ULN)] levels at the time of biopsy: (a) hepatocellular pattern(H), > 5; (b) mixed pattern(M),2-5; (c) cholestatic pattern(C), < 2. OUTCOMES: (a) histological evaluation of the single components of NAS, MASH, and fibrosis; (b) NITs and transient elastography assessing advanced fibrosis; (c) prognosis determined by the appearance of decompensated cirrhosis and death. RESULTS: Out of the 2156 patients, 22.9% exhibited the H-pattern, whilst 31.7% exhibited the C-pattern. Severe steatosis, ballooning, lobular inflammation, and MASH (56.4% H vs. 41.9% M vs. 31.9% C) were more common in H-pattern (p = 0.0001),whilst C-pattern was linked to cirrhosis (5.8% H vs. 5.6% M vs. 10.9% C; p = 0.0001). FIB-4(0.74(95% CI 0.69-0.79) vs. 0.83 (95% CI 0.80-0.85); p = 0.005) and Hepamet Fibrosis Score(0.77 (95% CI 0.69-0.85) vs. 0.84 (95% CI 0.80-0.87); p = 0.044)exhibited lower AUROCs in the H-pattern. The C-pattern[HR 2.37 (95% CI 1.12-5.02); p = 0.024], along with age, diabetes, and cirrhosis were independently associated with mortality. Most patients maintained their initial biochemical pattern during the second evaluation. CONCLUSIONS: The H-pattern exhibited greater necro-inflammation in the histology than the C-pattern, whereas the latter showed more cirrhosis. The accuracy of NITs in detecting fibrosis was decreased in H-pattern. The occurrence of decompensated events and mortality was predominant in C-pattern. Therefore, identifying MASLD phenotypes based on the biochemical presentation could be relevant for clinical practice.

Fibrosis avanzada asociada a esteatohepatitis no alcohólica (NASH) en España: resultados de un estudio Delphi / Advanced fibrosis associated with non-alcoholic steatohepatitis (NASH) in Spain: results of a Delphi study

Objetivo: Describir de manera detallada la epidemiología, diagnóstico, manejo clínico, opciones de tratamiento, impacto en la calidad de vida y necesidades no cubiertas de los pacientes con fibrosis hepática avanzada (F3-F4) asociada a esteatohepatitis no alcohólica (NASH) en España. Metodología: Estudio Delphi de dos rondas de consulta con 41 hepatólogos expertos de 16 comunidades autónomas para recoger su experiencia en práctica clínica. Resultados: La prevalencia estimada de pacientes adultos diagnosticados de fibrosis F3-F4 asociada a NASH en España es de 0,019% (intervalo de confianza [IC] 95%: 0,019-0,020%). Aproximadamente 7.588 adultos con este padecimiento están actualmente diagnosticados y son manejados en los Servicios de Aparato Digestivo de los hospitales españoles, y alrededor de 1.881 nuevos pacientes son diagnosticados cada año. El manejo es multidisciplinar e incluye las especialidades de Aparato Digestivo, Endocrinología y Medicina interna, considerando las frecuentes comorbilidades metabólicas asociadas (obesidad, diabetes mellitus tipo 2 o sobrecarga férrica dismetabólica). A pesar del claro impacto en la calidad de vida, este no se evalúa rutinariamente en la práctica clínica. Las técnicas diagnósticas no invasivas más utilizadas son la elastografía de transición y el índice de fibrosis hepática 4 (FIB-4). La ausencia de tratamientos eficaces y seguros se presenta como la principal necesidad no cubierta para el manejo de estos pacientes. Conclusiones: Este estudio proporciona una representación de la situación actual de los pacientes diagnosticados con fibrosis F3-F4 asociada a NASH en España, incrementando la evidencia disponible y contribuyendo a la toma de decisiones informadas por parte de los profesionales y el sistema sanitario. (AU)

Objective: To describe in detail the epidemiology, diagnosis, clinical management, treatment options, impact on quality of life and unmet needs of patients with advanced liver fibrosis (F3-F4) associated with non-alcoholic steatohepatitis (NASH) in Spain. Methodology: Delphi study of two rounds of consultation rounds with 41 expert hepatologists from 16 autonomous communities to collect their experience in clinical practice. Results: The estimated prevalence of adult patients diagnosed with F3-F4 fibrosis associated with NASH in Spain is 0.019% (95% confidence interval [CI]: 0.019-0.020%). Approximately 7,588 adults with this condition are currently diagnosed and managed in the Digestive System Services of Spanish hospitals, and around 1,881 new patients are diagnosed each year. Management is multidisciplinary and includes the specialties of Digestive System, Endocrinology and Internal Medicine, considering the frequently associated metabolic comorbidities (obesity, type 2 diabetes mellitus or dysmetabolic iron overload). Despite a clear impact on quality of life, this it is not routinely evaluated in clinical practice. The most widely used non-invasive diagnostic techniques are transitional elastography and liver fibrosis index 4 (FIB-4). The absence of effective and safe treatments appears as the main unmet need for the management of these patients. Conclusions: This study provides a representation of the current situation of patients diagnosed with F3-F4 fibrosis associated with NASH in Spain, increasing the evidence available and contributing to informed decision-making by professionals and the health system. (AU)

Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease.

OBJECTIVE: Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death. DESIGN: We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell's C-index and its improvement by including ferritin as a covariate. RESULTS: Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 µg/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 µg/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 µg/L and 272 µg/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65). CONCLUSIONS: This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD.

Serum identification of at-risk MASH: The metabolomics-advanced steatohepatitis fibrosis score (MASEF).

BACKGROUND: Early identification of those with NAFLD activity score ≥ 4 and significant fibrosis (≥F2) or at-risk metabolic dysfunction-associated steatohepatitis (MASH) is a priority as these patients are at increased risk for disease progression and may benefit from therapies. We developed and validated a highly specific metabolomics-driven score to identify at-risk MASH. METHODS: We included derivation (n = 790) and validation (n = 565) cohorts from international tertiary centers. Patients underwent laboratory assessment and liver biopsy for metabolic dysfunction-associated steatotic liver disease. Based on 12 lipids, body mass index, aspartate aminotransferase, and alanine aminotransferase, the MASEF score was developed to identify at-risk MASH and compared to the FibroScan-AST (FAST) score. We further compared the performance of a FIB-4 + MASEF algorithm to that of FIB-4 + liver stiffness measurements (LSM) by vibration-controlled transient elastography (VCTE). RESULTS: The diagnostic performance of the MASEF score showed an area under the receiver-operating characteristic curve, sensitivity, specificity, and positive and negative predictive values of 0.76 (95% CI 0.72-0.79), 0.69, 0.74, 0.53, and 0.85 in the derivation cohort, and 0.79 (95% CI 0.75-0.83), 0.78, 0.65, 0.48, and 0.88 in the validation cohort, while FibroScan-AST performance in the validation cohort was 0.74 (95% CI 0.68-0.79; p = 0.064), 0.58, 0.79, 0.67, and 0.73, respectively. FIB-4+MASEF showed similar overall performance compared with FIB-4 + LSM by VCTE ( p = 0.69) to identify at-risk MASH. CONCLUSION: MASEF is a promising diagnostic tool for the assessment of at-risk MASH. It could be used alternatively to LSM by VCTE in the algorithm that is currently recommended by several guidance publications.

Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol.

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721.

Advanced fibrosis associated with non-alcoholic steatohepatitis (NASH) in Spain: results of a Delphi study. / Fibrosis avanzada asociada a esteatohepatitis no alcohólica (NASH) en España: resultados de un estudio Delphi.

OBJECTIVE: To describe in detail the epidemiology, diagnosis, clinical management, treatment options, impact on quality of life and unmet needs of patients with advanced liver fibrosis (F3-F4) associated with non-alcoholic steatohepatitis (NASH) in Spain. METHODOLOGY: Delphi study of two rounds of consultation rounds with 41 expert hepatologists from 16 autonomous communities to collect their experience in clinical practice. RESULTS: The estimated prevalence of adult patients diagnosed with F3-F4 fibrosis associated with NASH in Spain is 0.019% (95% confidence interval [CI]: 0.019-0.020%). Approximately 7,588 adults with this condition are currently diagnosed and managed in the Digestive System Services of Spanish hospitals, and around 1,881 new patients are diagnosed each year. Management is multidisciplinary and includes the specialties of Digestive System, Endocrinology and Internal Medicine, considering the frequently associated metabolic comorbidities (obesity, type 2 diabetes mellitus or dysmetabolic iron overload). Despite a clear impact on quality of life, this it is not routinely evaluated in clinical practice. The most widely used non-invasive diagnostic techniques are transitional elastography and liver fibrosis index 4 (FIB-4). The absence of effective and safe treatments appears as the main unmet need for the management of these patients. CONCLUSIONS: This study provides a representation of the current situation of patients diagnosed with F3-F4 fibrosis associated with NASH in Spain, increasing the evidence available and contributing to informed decision-making by professionals and the health system.

Role of EpCAM+ CD133+ extracellular vesicles in steatosis to steatohepatitis transition in NAFLD.

BACKGROUND AND AIMS: Extracellular vesicles (EVs) have emerged as a potential source of circulating biomarkers in liver disease. We evaluated circulating AV+ EpCAM+ CD133+ EVs as a potential biomarker of the transition from simple steatosis to steatohepatitis. METHODS: EpCAM and CD133 liver proteins and EpCAM+ CD133+ EVs levels were analysed in 31 C57BL/6J mice fed with a chow or high fat, high cholesterol and carbohydrates diet (HFHCC) for 52 weeks. The hepatic origin of MVs was addressed using AlbCrexmT/mG mice fed a Western (WD) or Dual diet for 23 weeks. Besides, we assessed plasma MVs in 130 biopsy-proven NAFLD patients. RESULTS: Hepatic expression of EpCAM and CD133 and EpCAM+ CD133+ EVs increased during disease progression in HFHCC mice. GFP+ MVs were higher in AlbCrexmT/mG mice fed a WD (5.2% vs 12.1%) or a Dual diet (0.5% vs 7.3%). Most GFP+ MVs were also positive for EpCAM and CD133 (98.3% and 92.9% respectively), suggesting their hepatic origin. In 71 biopsy-proven NAFLD patients, EpCAM+ CD133+ EVs were significantly higher in those with steatohepatitis compare to those with simple steatosis (286.4 ± 61.9 vs 758.4 ± 82.3; p < 0.001). Patients with ballooning 367 ± 40.6 vs 532.0 ± 45.1; p = 0.01 and lobular inflammation (321.1 ± 74.1 vs 721.4 ± 80.1; p = 0.001), showed higher levels of these EVs. These findings were replicated in an independent cohort. CONCLUSIONS: Circulating levels of EpCAM+ CD133+ MVs in clinical and experimental NAFLD were increased in the presence of steatohepatitis, showing high potential as a non-invasive biomarker for the evaluation and management of these patients.

Relación del polimorfismo del gen de la resistina (rs7139228) con los niveles de resistina y el riesgo de síndrome metabólico en sujetos obesos / Relationship of resistin gene polymorphism (rs7139228) with resistin levels and metabolic syndrome risk in obese subjects

Antecedentes: a pesar de la relación de la resistina con el síndrome metabólico (SM), no se ha evaluado la relación del polimorfismo de nucleótido único (SNP) rs7139228 con variante C/T del intrón 5´UTR del gen RETN con la presencia de SM. Objetivo: el objetivo del presente estudio es evaluar la influencia del SNP rs7139228 del gen RETN sobre las concentraciones de resistina circulante, así como sobre el SM en sujetos obesos. Material y métodos: se reclutó una población caucásica de 1003 sujetos obesos. En todos los sujetos se realizó un análisis antropométrico (peso, perímetro de cintura, masa grasa), una evaluación de la ingesta nutricional, un estudio bioquímico (glucosa, insulina, proteína C-reactiva, perfil lipídico, insulina, HOMA-IR, resistina) y una evaluación del genotipo rs7139228. Resultados: la distribución del genotipo fue la siguiente: 852 sujetos con GG (84,9 %), 147 sujetos con GA (14,7 %) y 4 sujetos con AA (0,4 %). La frecuencia alélica fue G (0,92) y C (0,08). Las concentraciones séricas de resistina (delta: 1,7 ± 0,2 ng/ml; p = 0,01), insulina (delta: 4,2 ± 0,4 UI/L; p = 0,01) y HOMA-IR (delta: 1,9 ± 0,2 unidades; p = 0,03) fueron mayores en los pacientes portadores del alelo A que en los no portadores. La prevalencia global del SM fue del 48,1 %. El análisis de regresión logística mostró un alto porcentaje de hiperglucemia (OR = 1,60, IC 95 % = 1,08-2,96; p = 0,02) y de síndrome metabólico (OR = 1,33, IC 95 % = 1,07-3,39; p = 0,02) en los portadores del alelo A después de ajustar las concentraciones de resistina, el sexo, el IMC y la edad. Conclusiones: el alelo A de la variante genética rs7139228 se asocia con mayores niveles de resistina, insulina basal, resistencia a la insulina y prevalencia de síndrome metabólico en sujetos obesos. (AU)

Background: despite the relationship of resistin with metabolic syndrome (MS), the relationship of the 5’UTR intron C/T variant single nucleotide ploymorphism (SNP) rs7139228 of the RETN gene with the presence of MS has not been evaluated. Objective: the objective of this study is to evaluate the influence of SNP rs7139228 of the RETN gene on circulating resistin levels, as well as on MS in obese subjects. Material and methods: a Caucasian population of 1003 obese subjects was enrolled. An anthropometric evaluation (weight, waist circumference, fat mass), evaluation of nutritional intake, biochemical study (glucose, insulin, C-reactive protein, lipid profile, insulin, HOMA-IR, resistin) and rs7139228 genotype was carried out. Results: genotype distribution was: 852 subjects with GG (84.9 %), 147 subjects with GA (14.7 %) and 4 subjects with AA (0.4 %). The allelic frequency was G (0.92) and A (0.08). Serum levels of resistin (delta: 1.7 ± 0.2 ng/ml; p = 0.01), insulin (delta: 4.2 ± 0.4 IU/L; p = 0.01) and HOMA-IR (delta: 1.9 ± 0.2 units; p = 0.03) were higher in patients carrying the A allele than in non-carriers. The overall prevalence of MS was 48.1 %. A logistic regression analysis showed a high percentage of hyperglycemia (OR = 1.60, 95 % CI = 1.08-2.96; p = 0.02) and metabolic syndrome (OR = 1.33, 95 % CI = 1.07-3.39, p = 0.02) in carriers of the A allele after adjusting for resistin levels, sex, BMI and age. Conclusions: the A allele of the genetic variant rs7139228 is associated with higher levels of resistin, basal insulin, insulin resistance, and prevalence of metabolic syndrome in obese subjects. (AU)

Role of resistin (rs7139228) gene polymorphism with metabolic response after a hypocaloric mediterranean diet.

BACKGROUND: The SNP (rs7139228) of the RETN gene is a polymorphism that has been associated with metabolic disorder in subjects with obesity, and its effect on metabolic response after dietary intervention has not been evaluated. OBJECTIVE: Our objective was to analyse the effects of the polymorphism of the RETN gene rs7139228 on metabolic changes secondary to weight loss with a hypocaloric Mediterranean diet. DESIGN: 1000 obese Caucasian patients were evaluated. An anthropometric evaluation and a biochemical analysis were performed before and after 12 weeks of a hypocaloric Mediterranean diet. The statistical analysis was performed as a dominant model (GG vs GA+AA). RESULTS: Improvements in anthropometric parameters, leptin levels and systolic blood pressure were similar in both genotype groups. In non- A allele carriers, levels of resistin, insulin, HOMA-IR, triglycerides and C-reactive protein decreased. The improvements were statistically significant in this group; resistin (-1.3+0.1ng/dL: p=0.02), triglycerides (-22.9+4.9mg/dl: p=0.02), CRP (-2.7+0 0.4mg/dl: p=0.02), insulin -6.5+1.8 mIU/L: p=0.02) and HOMA-IR (-2.2+0.8: p=0, 03). In addition, insulin, HOMA-IR and resistin levels were higher in A allele carriers than in non-carriers. Finally, the prevalence of metabolic syndrome and hyperglycaemia were higher in A allele carriers, and these percentages only decreased after intervention in non-A allele carriers. CONCLUSION: The A rs7139228 allele is associated with a worse metabolic response (insulin, HOMA-IR, triglycerides and CRP) after weight loss with a hypocaloric Mediterranean diet. A non-significant decrease in the prevalence of metabolic syndrome and hyperglycaemia were detected in A allele carriers.

Association of the leptin receptor rs1805134 polymorphism with obesity parameters, dietary intakes, and metabolic syndrome in Caucasian obese subjects / Asociación del polimorfismo del receptor de leptina rs 1805134 con parámetros de obesidad, ingesta alimentaria y síndrome metabólico en sujetos caucásicos con obesidad

Background: some studies have evaluated the association of the rs1805134 genetic variant of the LEPR gene with obesity. Aims: the objective was to explore the association of the rs1805134 genetic variant of the LEPR gene with obesity measures and metabolic syndrome in obese Caucasian adults. Methods: we conducted a cross-sectional study in 212 obese subjects with body mass index (BMI) greater than 30 kg/m2. Measurements of adiposity parameters, blood pressure, fasting blood glucose, insulin concentration, insulin resistance (HOMA-IR), lipid profile, C-reactive protein, and prevalence of metabolic syndrome were determined. Results: the distribution of rs1805134 was 128 TT (60.4 %), 77 TC (36.3 %), and 7 CC (3.3 %). C-allele carriers showed higher levels of BMI, body weight, body fat mass, waist circumference, insulin, HOMA-IR, triglycerides, total energy intake, and carbohydrate intake than non-C-allele carriers. A logistic regression analysis reported a high percentage of elevated waist circumference (OR = 2.22, 95 % CI = 1.201-4.97; p = 0.02), hyperglycemia (OR = 1.54, 95 % CI = 1.01-5.44; p = 0.01), and metabolic syndrome percentage (OR = 1.41, 95 % CI = 1.04-5.39; p = 0.03) in C-allele carriers. Conclusions: subjects with the C-allele of the rs1805134 variant of the LEPR gene showed a worse metabolic pattern with a higher percentage of metabolic syndrome, central obesity and hyperglycaemia, probably related to higher energy intake. (AU)

Antecedentes: algunos estudios han evaluado la asociación de la variante genética rs1805134 del gen LEPR con la obesidad. Objetivos: el objetivo fue explorar la asociación de la variante genética rs1805134 del gen LEPR con los parámetros de obesidad y síndrome metabólico en adultos caucásicos obesos. Métodos: realizamos un estudio transversal en 212 sujetos obesos con índice de masa corporal (IMC) superior a 30 kg/m2 . Se determinaron los parámetros de adiposidad, presión arterial, glucemia en ayunas, concentración de insulina, resistencia a la insulina (HOMA-IR), perfil lipídico, proteína C-reactiva y prevalencia de síndrome metabólico. Resultados: la distribución del rs1805134 fue de 128 TT (60,4 %), 77 TC (36,3 %) y 7 CC (3,3 %). Los portadores del alelo C mostraron niveles más altos de IMC, peso corporal, masa grasa corporal, circunferencia de la cintura, insulina, HOMA-IR, triglicéridos, ingesta total de energía y consumo de carbohidratos que los portadores sin alelo C. El análisis de regresión logística mostró un alto porcentaje de pacientes con elevada circunferencia de la cintura (OR = 2,22, IC 95 % = 1,201-4,97; p = 0,02), hiperglucemia (OR = 1,54, IC 95 % = 1,01-5,44; p = 0,01) y síndrome metabólico (OR = 1,41, IC 95 % = 1,04-5,39; p = 0,03) en los portadores del alelo C. Conclusiones: los sujetos con alelo C de la variante rs1805134 del gen LEPR mostraron un peor patrón metabólico con mayor porcentaje de síndrome metabólico, obesidad central e hiperglucemia, probablemente relacionado con una mayor ingesta energética. (AU)

Dietary intervention with 2 different fat profiles; role of the rs822393 variant in metabolic parameter changes / Intervención dietética con 2 perfiles diferentes de grasa; papel de la variante rs822393en la modificación de parámetros metabólicos

Introduction: rs822393 is related to dietary intervention responses. The aim of our study was to analyze the metabolic effects of 2 hypocaloric diets with a different fat profile during 3 months according to the genetic variant rs822393. Methods: a population of 361 obese patients were randomly allocated to one of two diets; Diet P (enriched in polyunsaturated fatty acids) vs. Diet M (enriched in monounsaturated fatty acids). Adiposity and biochemical parameters were determined. rs822393 was assessed by real-time PCR, with a dominant model analysis (CC vs CT+TT). Results: genotype distribution was: 221 CC (61.2 %), 115 CT (31.9 %) and 25 TT (6.9 %). Basal and post-intervention HDL cholesterol, adiponectin levels and adiponectin/leptin ratio were lower in T-allele than non-T-allele carriers. After both diets, BMI, weight, fat mass, waist circumference, systolic blood pressure, insulin levels, HOMA-IR, leptin, total cholesterol and LDL-cholesterol improved significantly in both genotype groups. After Diet P, HDL-cholesterol (delta: 5.6 ± 1.1 mg/dl vs. 2.7 ± 0.9 mg/dl; p = 0.01), serum adiponectin (20.1 ± 2.9 ng/dl vs. 6.8 ± 3.0 ng/dl; p = 0.02) and adiponectin/leptin ratio (0.57 ± 0.1 units vs. 0.20 ± 0.08 units; p = 0.03) improved in non-T allele carriers. The same improvements were observed after Diet M: HDL-cholesterol (delta: 5.5 ± 0.8 mg/dl vs. 3.1 ± 0.9 mg/dl; p = 0.03), serum adiponectin (19.5 ± 2.9 ng/dl vs. 4.5 ± 2.8 ng/dl; p = 0.01), and adiponectin/leptin ratio (0.54 ± 0.1 units vs. 0.15 ± 0.08 units; p = 0.03). These parameters remained unchanged in T-allele carriers. (AU)

Introducción: el polimorfismo rs822393 está relacionado con las respuestas a las intervenciones dietéticas. El objetivo de nuestro estudio fue analizar los efectos metabólicos de 2 dietas hipocalóricas con diferente perfil graso durante 3 meses según la variante genética rs822393. Métodos: una muestra de 361 pacientes obesos se asignó aleatoriamente a una de dos dietas: dieta P (enriquecida en ácidos grasos poliinsaturados) y dieta M (enriquecida en ácidos grasos monoinsaturados). Se determinaron parámetros de adiposidad y bioquímicos; rs822393 se evaluó mediante PCR en tiempo real, con un análisis de modelo dominante (CC frente a CT+TT). Resultados: la distribución del genotipo fue: 221 CC (61,2 %), 115 CT (31,9 %) y 25 TT (6,9 %). El colesterol HDL basal y posterior a la intervención, los niveles de adiponectina y la relación adiponectina/leptina fueron más bajos en los portadores del alelo T que en los no portadores del alelo T. Tras la intervención con ambas dietas, el IMC, el peso, la masa grasa, la circunferencia de la cintura, la presión arterial sistólica, los niveles de insulina, el HOMA-IR, la leptina, el colesterol total y el colesterol LDL mejoraron significativamente en ambos grupos de genotipo. Después de la dieta P: HDL-colesterol (delta: 5,6 ± 1,1 mg/dl vs. 2,7 ± 0,9 mg/dl; p = 0,01), adiponectina sérica (20,1 ± 2,9 ng/dl vs. 6,8 ± 3,0 ng/dl; p = 0,02) y la relación adiponectina/leptina (0,57 ± 0,1 unidades frente a 0,20 ± 0,08 unidades; p = 0,03) mejoraron en los no portadores del alelo T. Se observaron los mismos resultados después de la dieta M: HDL-colesterol (delta: 5,5 ± 0,8 mg/dl frente a 3,1 ± 0,9 mg/dl; p = 0,03), adiponectina sérica (19,5 ± 2,9 ng/dl frente a 4,5 ± 2,8 ng /dl; p = 0,01) y relación adiponectina/leptina (0,54 ± 0,1 unidades vs. 0,15 ± 0,08 unidades; p = 0,03). Estos parámetros permanecieron sin cambios en los portadores del alelo T. (AU)

Relationship of resistin gene polymorphism (rs7139228) with resistin levels and metabolic syndrome risk in obese subjects.

Introduction: Background: despite the relationship of resistin with metabolic syndrome (MS), the relationship of the 5'UTR intron C/T variant SNP rs7139228 of the RETN gene with the presence of MS has not been evaluated. Objective: the objective of this study is to evaluate the influence of SNP rs7139228 of the RETN gene on circulating resistin levels, as well as on MS in obese subjects. Material and Methods: a Caucasian population of 1003 obese subjects was enrolled. An anthropometric evaluation (weight, waist circumference, fat mass), evaluation of nutritional intake, biochemical study (glucose, insulin, C-reactive protein, lipid profile, insulin, HOMA-IR, resistin) and rs7139228 genotype was carried out. Results: genotype distribution was: 852 subjects with GG (84.9 %), 147 subjects with GA (14.7 %) and 4 subjects with AA (0.4 %). The allelic frequency was G (0.92) and A (0.08). Serum levels of resistin (delta: 1.7 ± 0.2 ng/ml; p = 0.01), insulin (delta: 4.2 ± 0.4 IU/L; p = 0.01) and HOMA-IR (delta: 1.9 ± 0.2 units; p = 0.03) were higher in patients carrying the A allele than in non-carriers. The overall prevalence of MS was 48.1 %. A logistic regression analysis showed a high percentage of hyperglycemia (OR = 1.60, 95 % CI = 1.08-2.96; p = 0.02) and metabolic syndrome (OR = 1.33, 95 % CI = 1.07-3.39, p = 0.02) in carriers of the A allele after adjusting for resistin levels, sex, BMI and age. Conclusions: the A allele of the genetic variant rs7139228 is associated with higher levels of resistin, basal insulin, insulin resistance, and prevalence of metabolic syndrome in obese subjects.

Introducción: Antecedentes: a pesar de la relación de la resistina con el síndrome metabólico (SM), no se ha evaluado la relación del SNP rs7139228 con variante C/T del intrón 5´UTR del gen RETN con la presencia de SM. Objetivo: el objetivo del presente estudio es evaluar la influencia del SNP rs7139228 del gen RETN sobre las concentraciones de resistina circulante, así como sobre el SM en sujetos obesos. Material y métodos: se reclutó una población caucásica de 1003 sujetos obesos. En todos los sujetos se realizó un análisis antropométrico (peso, perímetro de cintura, masa grasa), una evaluación de la ingesta nutricional, un estudio bioquímico (glucosa, insulina, proteína C-reactiva, perfil lipídico, insulina, HOMA-IR, resistina) y una evaluación del genotipo rs7139228. Resultados: la distribución del genotipo fue la siguiente: 852 sujetos con GG (84,9 %), 147 sujetos con GA (14,7 %) y 4 sujetos con AA (0,4 %). La frecuencia alélica fue G (0,92) y C (0,08). Las concentraciones séricas de resistina (delta: 1,7 ± 0,2 ng/ml; p = 0,01), insulina (delta: 4,2 ± 0,4 UI/L; p = 0,01) y HOMA-IR (delta: 1,9 ± 0,2 unidades; p = 0,03) fueron mayores en los pacientes portadores del alelo A que en los no portadores. La prevalencia global del SM fue del 48,1 %. El análisis de regresión logística mostró un alto porcentaje de hiperglucemia (OR = 1,60, IC 95 % = 1,08-2,96; p = 0,02) y de síndrome metabólico (OR = 1,33, IC 95 % = 1,07-3,39; p = 0,02) en los portadores del alelo A después de ajustar las concentraciones de resistina, el sexo, el IMC y la edad. Conclusiones: el alelo A de la variante genética rs7139228 se asocia con mayores niveles de resistina, insulina basal, resistencia a la insulina y prevalencia de síndrome metabólico en sujetos obesos.

Association of the leptin receptor rs 1805134 polymorphism with obesity parameters, dietary intakes, and metabolic syndrome in Caucasian obese subjects.

Introduction: Background: some studies have evaluated the association of the rs1805134 genetic variant of the LEPR gene with obesity. Aims: the objective was to explore the association of the rs1805134 genetic variant of the LEPR gene with obesity measures and metabolic syndrome in obese Caucasian adults. Methods: we conducted a cross-sectional study in 212 obese subjects with body mass index (BMI) greater than 30 kg/m2. Measurements of adiposity parameters, blood pressure, fasting blood glucose, insulin concentration, insulin resistance (HOMA-IR), lipid profile, C-reactive protein, and prevalence of metabolic syndrome were determined. Results: the distribution of rs1805134 was 128 TT (60.4 %), 77 TC (36.3 %), and 7 CC (3.3 %). C-allele carriers showed higher levels of BMI, body weight, body fat mass, waist circumference, insulin, HOMA-IR, triglycerides, total energy intake, and carbohydrate intake than non-C-allele carriers. A logistic regression analysis reported a high percentage of elevated waist circumference (OR = 2.22, 95 % CI = 1.201-4.97; p = 0.02), hyperglycemia (OR = 1.54, 95 % CI = 1.01-5.44; p = 0.01), and metabolic syndrome percentage (OR = 1.41, 95 % CI = 1.04-5.39; p = 0.03) in C-allele carriers. Conclusions: subjects with the C-allele of the rs1805134 variant of the LEPR gene showed a worse metabolic pattern with a higher percentage of metabolic syndrome, central obesity and hyperglycaemia, probably related to higher energy intake.

Introducción: Antecedentes: algunos estudios han evaluado la asociación de la variante genética rs1805134 del gen LEPR con la obesidad. Objetivos: el objetivo fue explorar la asociación de la variante genética rs1805134 del gen LEPR con los parámetros de obesidad y síndrome metabólico en adultos caucásicos obesos. Métodos: realizamos un estudio transversal en 212 sujetos obesos con índice de masa corporal (IMC) superior a 30 kg/m2. Se determinaron los parámetros de adiposidad, presión arterial, glucemia en ayunas, concentración de insulina, resistencia a la insulina (HOMA-IR), perfil lipídico, proteína C-reactiva y prevalencia de síndrome metabólico. Resultados: la distribución del rs1805134 fue de 128 TT (60,4 %), 77 TC (36,3 %) y 7 CC (3,3 %). Los portadores del alelo C mostraron niveles más altos de IMC, peso corporal, masa grasa corporal, circunferencia de la cintura, insulina, HOMA-IR, triglicéridos, ingesta total de energía y consumo de carbohidratos que los portadores sin alelo C. El análisis de regresión logística mostró un alto porcentaje de pacientes con elevada circunferencia de la cintura (OR = 2,22, IC 95 % = 1,201-4,97; p = 0,02), hiperglucemia (OR = 1,54, IC 95 % = 1,01-5,44; p = 0,01) y síndrome metabólico (OR = 1,41, IC 95 % = 1,04-5,39; p = 0,03) en los portadores del alelo C. Conclusiones: los sujetos con alelo C de la variante rs1805134 del gen LEPR mostraron un peor patrón metabólico con mayor porcentaje de síndrome metabólico, obesidad central e hiperglucemia, probablemente relacionado con una mayor ingesta energética.

Dietary intervention with 2 different fat profiles; role of the rs822393 variant in metabolic parameter changes.

Introduction: Introduction: rs822393 is related to dietary intervention responses. The aim of our study was to analyze the metabolic effects of 2 hypocaloric diets with a different fat profile during 3 months according to the genetic variant rs822393. Methods: a population of 361 obese patients were randomly allocated to one of two diets; Diet P (enriched in polyunsaturated fatty acids) vs. Diet M (enriched in monounsaturated fatty acids). Adiposity and biochemical parameters were determined. rs822393 was assessed by real-time PCR, with a dominant model analysis (CC vs CT+TT). Results: genotype distribution was: 221 CC (61.2 %), 115 CT (31.9 %) and 25 TT (6.9 %). Basal and post-intervention HDL cholesterol, adiponectin levels and adiponectin/leptin ratio were lower in T-allele than non-T-allele carriers. After both diets, BMI, weight, fat mass, waist circumference, systolic blood pressure, insulin levels, HOMA-IR, leptin, total cholesterol and LDL-cholesterol improved significantly in both genotype groups. After Diet P, HDL-cholesterol (delta: 5.6 ± 1.1 mg/dl vs. 2.7 ± 0.9 mg/dl; p = 0.01), serum adiponectin (20.1 ± 2.9 ng/dl vs. 6.8 ± 3.0 ng/dl; p = 0.02) and adiponectin/leptin ratio (0.57 ± 0.1 units vs. 0.20 ± 0.08 units; p = 0.03) improved in non-T allele carriers. The same improvements were observed after Diet M: HDL-cholesterol (delta: 5.5 ± 0.8 mg/dl vs. 3.1 ± 0.9 mg/dl; p = 0.03), serum adiponectin (19.5 ± 2.9 ng/dl vs. 4.5 ± 2.8 ng/dl; p = 0.01), and adiponectin/leptin ratio (0.54 ± 0.1 units vs. 0.15 ± 0.08 units; p = 0.03). These parameters remained unchanged in T-allele carriers. Conclusion: after two different hypocaloric diets, obese subjects with the T allele of rs822393 did not improve their adiponectin levels, ratio adiponectin/leptin, and HDL-cholesterol, despite loss of weight.

Introducción: Introducción: el polimorfismo rs822393 está relacionado con las respuestas a las intervenciones dietéticas. El objetivo de nuestro estudio fue analizar los efectos metabólicos de 2 dietas hipocalóricas con diferente perfil graso durante 3 meses según la variante genética rs822393. Métodos: una muestra de 361 pacientes obesos se asignó aleatoriamente a una de dos dietas: dieta P (enriquecida en ácidos grasos poliinsaturados) y dieta M (enriquecida en ácidos grasos monoinsaturados). Se determinaron parámetros de adiposidad y bioquímicos; rs822393 se evaluó mediante PCR en tiempo real, con un análisis de modelo dominante (CC frente a CT+TT). Resultados la distribución del genotipo fue: 221 CC (61,2 %), 115 CT (31,9 %) y 25 TT (6,9 %). El colesterol HDL basal y posterior a la intervención, los niveles de adiponectina y la relación adiponectina/leptina fueron más bajos en los portadores del alelo T que en los no portadores del alelo T. Tras la intervención con ambas dietas, el IMC, el peso, la masa grasa, la circunferencia de la cintura, la presión arterial sistólica, los niveles de insulina, el HOMA-IR, la leptina, el colesterol total y el colesterol LDL mejoraron significativamente en ambos grupos de genotipo. Después de la dieta P: HDL-colesterol (delta: 5,6 ± 1,1 mg/dl vs. 2,7 ± 0,9 mg/dl; p = 0,01), adiponectina sérica (20,1 ± 2,9 ng/dl vs. 6,8 ± 3,0 ng/dl; p = 0,02) y la relación adiponectina/leptina (0,57 ± 0,1 unidades frente a 0,20 ± 0,08 unidades; p = 0,03) mejoraron en los no portadores del alelo T. Se observaron los mismos resultados después de la dieta M: HDL-colesterol (delta: 5,5 ± 0,8 mg/dl frente a 3,1 ± 0,9 mg/dl; p = 0,03), adiponectina sérica (19,5 ± 2,9 ng/dl frente a 4,5 ± 2,8 ng /dl; p = 0,01) y relación adiponectina/leptina (0,54 ± 0,1 unidades vs. 0,15 ± 0,08 unidades; p = 0,03). Estos parámetros permanecieron sin cambios en los portadores del alelo T. Conclusión: tras las dos dietas hipocalóricas diferentes, los sujetos obesos con el alelo T de rs822393 no mejoraron los niveles de adiponectina, ratio adiponectina/leptina y colesterol HDL, a pesar de la pérdida de peso.

Role of Oxidative Stress and Lipid Peroxidation in the Pathophysiology of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is characterised by an excess of hepatic fat that can progress to steatohepatitis, fibrosis, cirrhosis and hepatocarcinoma. The imbalance between lipid uptake/lipogenesis and lipid oxidation/secretion in the liver is a major feature of NAFLD. Given the lack of a non-invasive and reliable methods for the diagnosis of non-alcoholic steatohepatitis (NASH), it is important to find serum markers that are capable of discriminating or defining patients with this stage of NASH. Blood samples were obtained from 152 Caucasian subjects with biopsy-proven NAFLD due to persistently elevated liver enzyme levels. Metabolites representative of oxidative stress were assessed. The findings derived from this work revealed that NAFLD patients with a NASH score of ≥ 4 showed significantly higher levels of lipid peroxidation (LPO). Indeed, LPO levels above the optimal operating point (OOP) of 315.39 µM are an independent risk factor for presenting a NASH score of ≥ 4 (OR: 4.71; 95% CI: 1.68−13.19; p = 0.003). The area under the curve (AUC = 0.81, 95% CI = 0.73−0.89, p < 0.001) shows a good discrimination ability of the model. Therefore, understanding the molecular mechanisms underlying the basal inflammation present in these patients is postulated as a possible source of biomarkers and therapeutic targets in NASH.

Dietary Recommendations for the Management of Non-alcoholic Fatty Liver Disease (NAFLD): A Nutritional Geometry Perspective.

Diet could be both culprit and solution of NAFLD. Dietary modifications have been associated with histological features improvement in NAFLD. The Western diet was related to a greater risk of disease progression while the Mediterranean diet (MD) could promote regression of histological lesions. Modifications in the nutrient composition seems to have lesser impact on NAFLD than dietary modifications. An intrinsic interaction between nutrients in the diet support a specific effect not seen when added separately. Dietary modifications should focus on promoting weight loss but also look for patterns that are able to promote histological improvement. Although several micronutrients' deficit has been related to NAFLD progression, prescribing these micronutrients' supplementation did not reach a positive impact. However, an enriching diet with specific nutrients could be useful, like olive oil supplemented in MD. Geometry of nutrition defines a framework to better understand the interaction between nutrients, foods, and dietetic pattern in the model of diseases and how we could approach taking into consideration the interaction between meals and disease features. After analyzing baseline diet and histological lesions, we could calculate the distance to optimal diet and to promote changes in lifestyle to reach all these goals. A standard MD menu would be recommended.

Association of the APOA-5 Genetic Variant rs662799 with Metabolic Changes after an Intervention for 9 Months with a Low-Calorie Diet with a Mediterranean Profile.

In cross-sectional studies, the genetic variant rs662799 of the APOA5 gene is associated with high serum triglyceride concentrations, and in some studies, the effect of short-term dietary interventions has been evaluated. The aim of the present investigation was to evaluate the role of this genetic variant in metabolic changes after the consumption of a low-calorie diet with a Mediterranean pattern for 9 months. A population of 269 Caucasian obese patients was recruited. Adiposity and biochemical parameters were measured at the beginning (basal level) and after 3 and 9 months of the dietary intervention. The rs662799 genotype was assessed with a dominant analysis (TT vs. CT + CC). The APOA5 variant distribution was: 88.1% (n = 237) (TT), 11.5% (n = 31) (TC) and 0.4% (n = 1) (CC). There were significant differences only in triglyceride levels at all times of the study between the genotype groups. After 3 and 9 months of dietary intervention, the following parameters improved in both genotype groups: adiposity parameters, systolic pressure, total cholesterol, LDL cholesterol, leptin, adiponectin and the leptin/adiponectin ratio. The intervention significantly decreased insulin levels, HOMA-IR and triglyceride levels in non-C allele carriers (Delta 9 months TT vs. TC + CC). i.e., insulin levels (delta: -3.8 + 0.3 UI/L vs. -1.2 + 0.2 UI/L; p = 0.02), HOMA-IR levels (delta: -1.2 + 0.2 units vs. -0.3 + 0.1 units; p = 0.02), triglyceride levels (delta: -19.3 + 4.2 mg/dL vs. -4.2 + 3.0 mg/dL; p = 0.02). In conclusion, non-C allele carriers of rs662799 of the APOA5 gene showed a decrease of triglyceride, insulin and HOMA-IR levels after consuming a low-calorie diet with a Mediterranean pattern; we did not observe this effect in C allele carriers, despite a significant weight loss.

Prevalence estimation of significant fibrosis because of NASH in Spain combining transient elastography and histology.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has become a major public health problem, but the prevalence of fibrosis associated with non-alcoholic steatohepatitis (NASH) is largely unknown in the general population. This study aimed to provide an updated estimation of the prevalence of NASH fibrosis in Spain. METHODS: This was an observational, retrospective, cross-sectional, population-based study with merged data from two Spanish datasets: a large (N = 12 246) population-based cohort (ETHON), including transient elastography (TE) data, and a contemporary multi-centric biopsy-proven NASH cohort with paired TE data from tertiary centres (N = 501). Prevalence for each NASH fibrosis stage was estimated by crossing TE data from ETHON dataset with histology data from the biopsy-proven cohort. RESULTS: From the patients with valid TE in ETHON dataset (N = 11 440), 5.61% (95% confidence interval [95% CI]: 2.53-11.97) had a liver stiffness measurement (LSM) ≥ 8 kPa. The proportion attributable to NAFLD (using clinical variables and Controlled Attenuation Parameter) was 57.3% and thus, the estimated prevalence of population with LSM ≥ 8 kPa because of NAFLD was 3.21% (95% CI 1.13-8.75). In the biopsy-proven NASH cohort, 389 patients had LSM ≥ 8 kPa. Among these, 37% did not have significant fibrosis (F2-4). The estimated prevalence of NASH F2-3 and cirrhosis in Spain's adult population were 1.33% (95% CI 0.29-5.98) and 0.70% (95% CI 0.10-4.95) respectively. CONCLUSIONS: These estimations provide an accurate picture of the current prevalence of NASH-related fibrosis in Spain and can serve as reference point for dimensioning the therapeutic efforts that will be required as NASH therapies become available.