Targeting metabolic-associated fatty liver disease in diabetic kidney disease: A call to action.

Nonalcoholic fatty liver disease or metabolic-associated fatty liver disease (MAFLD) is a common condicion with increasing prevalence and incidence, specially in patients with type 2 diabetes mellitus (T2DM). Both cardiovascular and renal disease are clearly increased in these patients, particularly in those with diabetic nephropathy. In the liver-heart-kidney-metabolic axis, the common pathophysiological basis of MAFLD, cardiovascular disease (CVD), chronic kidney disease (CKD), and T2DM is the same. The clinical relationship between all of them is clear and is multidirectional: MAFLD may precede the development of cardiovascular and renal disease, and may also worsen the prognosis of these complications once developed. In this review we emphasize the importance of targeting MAFLD in Diabetic kidney disease, with the goal of detecting high-risk patients in order to improve their prognosis.

Esteatosis hepática metabólica y nefropatía diabética: una llamada a la acción / Targeting metabolic-associated fatty liver disease in diabetic kidney disease: A call to action

La incidencia y la prevalencia de hígado graso no alcohólico o enfermedad hepática metabólica (EHmet) está en aumento y es mayor en pacientes con diabetes mellitus tipo 2 (DM2). El riesgo cardiovascular y renal está claramente incrementado en estos pacientes, especialmente cuando se desarrolla nefropatía diabética. El eje cardio-reno-hepato-metabólico, conformado por la enfermedad cardiovascular (ECV), la enfermedad renal crónica (ERC), la EHmet y la DM2, tiene una base fisiopatogénica común. La relación clínica entre todos los componentes es inevitable y multidireccional, pudiendo la EHmet preceder al desarrollo de complicaciones cardiovasculares y renales, y también empeorar el pronóstico de las mismas una vez desarrolladas. En esta revisión enfatizamos la importancia de buscar y tratar la EHmet en pacientes con ERC y DM2 con el objetivo de identificar pacientes de mayor riesgo y de mejorar su pronóstico.(AU)

Non-alcoholic fatty liver disease or metabolic-associated fatty liver disease (MAFLD) is a common condition with increasing prevalence and incidence, specially in patients with type 2 diabetes mellitus (DM2). Both cardiovascular and renal disease are clearly increased in these patients, particularly in those with diabetic nephropathy. In the liver–heart–kidney–metabolic axis, the common pathophysiological basis of MAFLD, cardiovascular disease (CVD), chronic kidney disease (CKD), and DM2 is the same. The clinical relationship between all of them is clear and is multidirectional: MAFLD may precede the development of cardiovascular and renal disease, and may also worsen the prognosis of these complications once developed. In this review we emphasize the importance of targeting MAFLD in diabetic kidney disease, with the goal of detecting high-risk patients in order to improve their prognosis.(AU)

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)

Cambios en las características epidemiológicas y en el pronóstico de la hepatitis crónica B en personas que viven con VIH / Epidemiological characteristic and prognosis changes in chronic hepatitis B in people living with HIV

Introducción: La vacunación, los avances en el tratamiento frente al virus de la hepatitis B (VHB) y los cambios epidemiológicos producidos en España en las últimas décadas han podido modificar las características y el pronóstico de la hepatitis crónica B (HCB) en personas que viven con VIH (PVIH). Métodos: Estudio observacional retrospectivo donde se incluyeron PVIH-HCB en seguimiento en una unidad de referencia madrileña hasta el año 2019. Se comparó la incidencia y las características epidemiológicas y clínicas según el momento del diagnóstico (antes del año 2000 y posteriormente en periodos de cinco años). Además, se realizó un estudio longitudinal retrospectivo evaluando la tasa de mortalidad, descompensación hepática y factores asociados. Resultados: De 5.452 PVIH, 160 presentaban HCB en el momento basal (prevalencia 2,92%, IC 95%: 2,5-3,4), 85,6% hombres, edad mediana al diagnóstico 32,1 (27-37,2) años. La incidencia (2,4/100 pacientes-año) no varió en los diferentes periodos. Los pacientes diagnosticados antes del 2000 (n = 87) comparados con los diagnosticados entre 2015-2019 (n = 11) con mayor frecuencia eran nativos españoles (90,8 vs. 18,2%), habían consumido drogas intravenosas (55,2 vs. 0), tenían antecedentes de hepatitis C (40 vs. 9,1%) y delta (30,4 vs. 0) y mayor afectación hepática (24,1% cirróticos vs. 0). Tras un seguimiento de 20,4 años, 23 pacientes murieron (7,1/1.000 pacientes-año) y 19 presentaron descompensación hepática (4,9/1.000 pacientes-año), todos diagnosticados antes del año 2010. La mortalidad se asoció con mayor fibrosis hepática basal estimada por Fibroscan® (HR 1,06; IC 95%: 1,03-1,09). Conclusión: Las PVIH-HCB con diagnóstico previo al año 2000 son más frecuentemente de nacionalidad española, infectadas por vía parenteral y con mayor prevalencia de otras coinfecciones. Los pacientes diagnosticados antes del 2010 tienen peor pronóstico condicionado por presentar mayor grado de fibrosis hepática.(AU)

Introduction: Due to hepatitis B virus (HBV) treatment and vaccination during the last decades in Spain, epidemiological and prognosis of chronic hepatitis B (CHB) may have changed. Methods: Retrospective review of CHB–HIV coinfected patients in a single reference center in Madrid until year 2019. We compared incidence, epidemiological and clinical characteristics according diagnosis period (before 2000, 2000–2004, 2005–2009, 2010–2014, 2015–2019). A retrospective longitudinal study was done to assess mortality, related risk factors and hepatic decompensation. Results: Out of 5452 PLHIV, 160 had CHB (prevalence 2.92%; 95% CI: 2.5–3.4), 85.6% were men, median age 32.1 (27–37.2). Incidence rate did not change over the years (2.4/100 patients-year). PLHIV with CHB diagnosed before year 2000 (n = 87) compared with those diagnosed between 2015 and 2019 (n = 11) were more often native-Spanish (90.8% vs. 18.2%), had infected using intravenous drugs (55.2% vs. 0), were coinfected with hepatitis C (40% vs. 9.1%) or hepatitis delta virus (30.4% vs. 0) and had more severe liver disease (cirrhosis 24.1% vs. 0). After a median follow-up of 20.4 years, 23 patients died (7.1/1000 patients-year) and 19 had liver decompensation (4.9/1000 patients-year). All deaths and liver decompensation occurred in patients diagnosed before year 2010. Mortality was associated with higher liver fibrosis in Fibroscan® (HR 1.06, 95% CI: 1.03–1.09). Conclusion: The epidemiology of CHB in PLHIV in our cohort is changing with less native Spanish, more sexually transmitted cases and less coinfection with other hepatotropic virus. Patients diagnosed before 2010 have worst prognosis related to higher grades of liver fibrosis.(AU)

GATA3 promotes the autophagy and activation of hepatic stellate cell in hepatic fibrosis via regulating miR-370/HMGB1 pathway / GATA3 promueve la autofagia y la activación de la célula estrellada hepática en la fibrosis hepática a través de la regulación de la vía miR-370/HMGB1

Background Hepatic fibrosis (HF) is a common result of the repair process of various chronic liver diseases. Hepatic stellate cells (HSCs) activation is the central link in the occurrence of HF. Methods ELISA and histological analysis were performed to detect the pathological changes of liver tissues. In vitro, HSCs were treated with TGF-β1 as HF cell model. Combination of GATA-binding protein 3 (GATA3) and miR-370 gene promoter was ensured by ChIP and luciferase reporter assay. Autophagy was monitored by observing the GFP-LC3 puncta formation. The interaction between miR-370 and high mobility group box 1 protein (HMGB1) was verified by luciferase reporter assay. Results CCl4-induced HF mice exhibited an increase of ALT and AST, and severe damage and fibrosis of liver tissues. GATA3 and HMGB1 were up-regulated, and miR-370 was down-regulated in CCl4-induced HF mice and activated HSCs. GATA3 enhanced expression of the autophagy-related proteins and activation markers in the activated HSCs. Inhibition of autophagy partly reversed GATA3-induced activation of HSCs and the promotion of GATA3 to hepatic fibrosis. Moreover, GATA3 suppressed miR-370 expression via binding with its promotor, and enhanced HMGB1 expression in HSCs. Increasing of miR-370 inhibited HMGB1 expression by directly targeting its mRNA 3′-UTR. The promotion of GATA3 to TGF-β1-induced HSCs autophagy and activation was abrogated by miR-370 up-regulation or HMGB1 knockdown. Conclusions This work demonstrates that GATA3 promotes autophagy and activation of HSCs by regulating miR-370/HMGB1 signaling pathway, which contributes to accelerate HF. Thus, this work suggests that GATA3 may be a potential target for prevention and treatment of HF. (AU)

Introducción La fibrosis hepática (IC) es un resultado común del proceso de reparación de diversas enfermedades hepáticas crónicas. La activación de las células estrelladas hepáticas (HSC) es el vínculo central en la aparición de insuficiencia cardíaca. Métodos Se realizaron ELISA y análisis histológicos para detectar los cambios patológicos de los tejidos hepáticos. In vitro, las HSC se trataron con TGF-1 como modelo de células HF. La combinación de la proteína 3 de unión a GATA (GATA3) y el promotor del gen miR-370 se aseguró mediante el ensayo ChIP y el indicador de luciferasa. La autofagia se controló observando la formación de puntos GFP-LC3. La interacción entre miR-370 y la proteína de la caja 1 del grupo de alta movilidad (HMGB1) se verificó mediante el ensayo indicador de luciferasa. Resultados Los ratones con HF inducida por CCl4 exhibieron un aumento de ALT y AST, y daño severo y fibrosis de los tejidos hepáticos. GATA3 y HMGB1 estaban regulados positivamente, y miR-370 estaba regulado negativamente en ratones HF inducidos por CCl4 y HSC activadas. GATA3 mejoró la expresión de las proteínas relacionadas con la autofagia y los marcadores de activación en las HSC activadas. La inhibición de la autofagia revirtió parcialmente la activación de HSC inducida por GATA3 y la promoción de GATA3 a la fibrosis hepática. Además, GATA3 suprimió la expresión de miR-370 mediante la unión con su promotor y mejoró la expresión de HMGB1 en HSC. El aumento de miR-370 inhibió la expresión de HMGB1 al apuntar directamente a su ARNm 3 -UTR. La promoción de GATA3 a la autofagia y activación de las HSC inducidas por TGF-1 fue anulada por la regulación positiva de miR-370 o la eliminación de HMGB1. Conclusiones Este trabajo demuestra que GATA3 promueve la autofagia y la activación de las HSC mediante la regulación de la vía de señalización de miR-370/HMGB1, lo que contribuye para acelerar la HF... (AU)

Epidemiological characteristic and prognosis changes in chronic hepatitis B in people living with HIV.

INTRODUCTION: Due to hepatitis B virus (HBV) treatment and vaccination during the last decades in Spain, epidemiological and prognosis of chronic hepatitis B (CHB) may have changed. METHODS: Retrospective review of CHB-HIV coinfected patients in a single reference center in Madrid until year 2019. We compared incidence, epidemiological and clinical characteristics according diagnosis period (before 2000, 2000-2004, 2005-2009, 2010-2014, 2015-2019). A retrospective longitudinal study was done to assess mortality, related risk factors and hepatic decompensation. RESULTS: Out of 5452 PLHIV, 160 had CHB (prevalence 2.92%; 95%CI 2.5-3.4), 85.6% were men, median age 32.1 (27-37.2). Incidence rate did not change over the years (2.4/100 patients-year). PLHIV with CHB diagnosed before year 2000 (n = 87) compared with those diagnosed between 2015 and 2019 (n = 11) were more often native-Spanish (90.8% vs. 18.2%), had infected using intravenous drugs (55.2% vs. 0), were coinfected with hepatitis C (40% vs. 9.1%) or hepatitis delta virus (30.4% vs. 0) and had more severe liver disease (cirrhosis 24.1% vs. 0). After a median follow-up of 20.4 years, 23 patients died (7.1/1000 patients-year) and 19 had liver decompensation (4.9/1000 patients-year). All deaths and liver decompensation occurred in patients diagnosed before year 2010. Mortality was associated with higher liver fibrosis in Fibroscan® (HR 1.06, 95% CI 1.03-1.09). CONCLUSION: The epidemiology of CHB in PLHIV in our cohort is changing with less native Spanish, more sexually transmitted cases and less coinfection with other hepatotropic virus. Patients diagnosed before 2010 have worst prognosis related to higher grades of liver fibrosis.

NAFLD and type 2 diabetes: A practical guide for the joint management / Esteatosis hepática metabólica y diabetes mellitus tipo 2: Una guía práctica para el manejo conjunto

Non-alcoholic fatty liver disease (NAFLD) is becoming a major cause of liver disease-related morbidity, as well as mortality. Importantly, NAFLD is considered a mediator of systemic diseases including cardiovascular disease. Its prevalence is expected to increase, mainly due to its close association with obesity and type 2 diabetes mellitus (T2D). In addition, T2D and NAFLD share common pathophysiological mechanisms, and one can lead to or worsen the other. Therefore, a close collaboration between primary care physician, endocrinologists and hepatologists is essential to optimize the management of patients with NAFLD and T2D. Here, we summarize relevant aspects about NAFLD and T2D that all clinician managing these patients should know as well as current therapeutic options for the treatment of T2D associated with NAFLD. (AU)

La esteatosis hepática metabólica (EHmet) se está convirtiendo en una de las causas más importantes de morbimortalidad relacionada con las enfermedades hepáticas. Es importante destacar que la EHmet se considera un mediador de enfermedades sistémicas, incluidas las enfermedades cardiovasculares. Se espera que su prevalencia aumente, principalmente debido a su estrecha relación con la obesidad y la diabetes mellitus tipo 2 (DM2). Además, la DM2 y la EHmet comparten mecanismos fisiopatológicos comunes y una puede provocar o empeorar la otra. Por lo tanto, una estrecha colaboración entre el médico de atención primaria, endocrinólogos y hepatólogos es fundamental para optimizar el manejo de los pacientes con EHmet y DM2. En esta guía resumimos aspectos relevantes sobre EHmet y DM2 que todo médico que maneja a estos pacientes debe conocer, así como las opciones terapéuticas actuales para el tratamiento de DM2 asociada a EHmet. (AU)

Prediction of clinical events by liver stiffness and chronic kidney disease by NAFLD in patients with type-2 diabetes / Predicción de eventos clínicos por elasticidad hepática y enfermedad renal crónica por EHMet en pacientes con diabetes tipo 2

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is associated with poorer glycemic control and a higher risk of type-2 diabetes (T2D) complications, extrahepatic and cardiovascular disease (CVD). Our study aim was to evaluate the association between NAFLD, T2D complications, and the development of overall clinical events (OCE) (CV, liver-related, and mortality) in patients with T2D. Methods: Prospective single-center study comprising T2D subjects with no history of CVD and non-T2D matched controls. Patients were selected from the Outpatient Diabetes Clinic of Vall d’Hebron Hospital and related primary care centers. Results: 186 diabetics and 57 controls were included. Amongst T2D, 124/186 subjects had NAFLD (66.6%). T2D-NAFLD subjects showed a heavier metabolic burden and higher median liver stiffness (5.6kPa [4.5–7.3] vs 4.8 [4.2–5.8]; p=0.004) compared to non-NAFLD diabetics. During a median follow-up of 5.6 years, 33 (17.7%) T2D patients developed OCE vs 4 (7.0%) controls (p=0.049). No differences were found for OCE between NAFLD and non-NAFLD diabetics (16.9% vs 19.4%; p=0.68). CV was the most reported outcome and only one liver event occurred. NAFLD diabetics showed more often chronic kidney disease (CKD), whereas T2D complications and subclinical CVD rates were similar. A higher liver stiffness, older age, and male gender were independently associated with OCE amongst the entire T2D population and NAFLD diabetics. Conclusions: NAFLD and liver stiffness were associated with CKD and clinical outcomes in diabetics, respectively. A hepatic evaluation is recommended to identify high-risk T2D patients that would benefit from early referral to specialized care. (AU)

Antecedentes y objetivos: La esteatosis hepática metabólica (EHMet) se asocia con un peor control glucémico y un mayor riesgo de complicaciones de la diabetes tipo 2 (DM2), enfermedad extrahepática y cardiovascular (CV). El objetivo fue evaluar la asociación entre EHMet, complicaciones microvasculares y el desarrollo de eventos clínicos globales (ECG) (CV, hepáticos y mortalidad) en diabéticos. Métodos: Estudio unicéntrico prospectivo que incluye diabéticos sin historia de CV y controles sin DM2. Se seleccionaron pacientes de la consulta de Diabetes del Hospital Vall d’Hebron y centros de atención primaria asociados. Resultados: Se incluyeron 186 diabéticos y 57 controles. Entre los diabéticos, 124/186 presentaron EHMet (66,6%). Los pacientes DM2 con EHMet presentaron mayor carga metabólica y una elasticidad hepática superior (5,6kPa [4,5-7,3] vs. 4,8 [4,2-5,8]; p=0,004) a los diabéticos sin EHMet. Durante una mediana de seguimiento de 5,6 años, 33 (17,7%) diabéticos desarrollaron ECG vs. 4 (7,0%) controles (p=0,049). No hubo diferencias en ECG entre diabéticos con y sin EHMet (16,9% vs. 19,4%; p=0,68). El evento más reportado fue CV y solamente se produjo un evento hepático. La enfermedad renal crónica (ERC) fue más frecuente en diabéticos con EHMet, mientras que los ratios de complicaciones microvasculares y enfermedad CV silente fueron similares. El género masculino, una mayor edad y elasticidad hepática se asociaron de forma independiente a ECG para el total de diabéticos y para aquellos con EHMet. Conclusiones: La EHMet y la elasticidad hepática se asociaron a ERC y eventos clínicos en diabéticos. Se recomienda una evaluación hepática para identificar pacientes diabéticos de riesgo que se beneficiarían de una derivación precoz al especialista. (AU)

Assessment of liver fibrosis in patients with rheumatoid arthritis treated with methotrexate: Utility of fibroscan and biochemical markers in routine clinical practice.

OBJECTIVES: To study the prevalence of liver fibrosis (LF) measured by FibroScan and APRI index in patients with rheumatoid arthritis (AR) undergoing treatment with methotrexate (MTX). METHODS: We included 59 patients with RA on MTX. Medical records, FibroScan measures and serological markers of liver damage were compared on the basis of cumulative methotrexate dose. RESULTS: Mean treatment duration was 82.4±65.1 months and mean cumulative dose was 5214.5±4031.9mg. Five patients met LF criteria by fibroscan, while only one patient had a suggestive APRI score. No statistically significant differences were found in terms of LF measured by both APRI and fibroScan between patients with cumulative doses above and below 4000mg. There was also no relationship between LF and treatment duration. CONCLUSIONS: The occurrence of LF in patients with RA on MTX is a multifactorial process that does not seem directly related to its cumulative dose. FibroScan may be a useful technique in clinical practice to screen for this complication.

Assessment of liver fibrosis in patients with rheumatoid arthritis treated with methotrexate: Utility of fibroscan and biochemical markers in routine clinical practice / Evaluación de la fibrosis hepática en pacientes con artritis reumatoide en tratamiento con metotrexato: utilidad en la práctica clínica habitual del FibroScan y marcadores bioquímicos

Objectives: To study the prevalence of liver fibrosis (LF) measured by FibroScan and APRI index in patients with rheumatoid arthritis (AR) undergoing treatment with methotrexate (MTX). Methods: We included 59 patients with RA on MTX. Medical records, FibroScan measures and serological markers of liver damage were compared on the basis of cumulative methotrexate dose. Results: Mean treatment duration was 82.4±65.1 months and mean cumulative dose was 5214.5±4031.9mg. Five patients met LF criteria by fibroscan, while only one patient had a suggestive APRI score. No statistically significant differences were found in terms of LF measured by both APRI and fibroScan between patients with cumulative doses above and below 4000mg. There was also no relationship between LF and treatment duration. Conclusions: The occurrence of LF in patients with RA on MTX is a multifactorial process that does not seem directly related to its cumulative dose. FibroScan may be a useful technique in clinical practice to screen for this complication. (AU)

Objetivos: Estudiar la prevalencia de la fibrosis hepática (FH) medida por FibroScan e índice APRI en pacientes con artritis reumatoide (AR) en tratamiento con metotrexato (MTX). Métodos: Se incluyeron 59 pacientes con AR en tratamiento con MTX. Se compararon las historias clínicas, las mediciones de FibroScan y los marcadores serológicos de daño hepático en función de la dosis acumulada de MTX. Resultados: La duración media del tratamiento fue de 82,4±65,1 meses y la dosis media acumulada de 5214,5±4031,9mg. Cinco pacientes cumplían criterios de FH por FibroScan y un solo paciente por APRI. No se encontraron diferencias estadísticamente significativas en cuanto a FH tanto por APRI como por FibroScan en base a dosis acumuladas superiores o inferiores a 4000mg. Tampoco hubo relación entre FH y duración del tratamiento. Conclusiones: La FH en pacientes con AR tratados con MTX es un proceso multifactorial sin aparente relación directa con la dosis acumulada. El FibroScan puede ser una técnica útil en la práctica clínica para detectar esta complicación. (AU)

Factores de riesgo de fibrosis avanzada en enfermedad hepática esteatósica asociada a disfunción metabólica en pacientes con diabetes mellitus 2

Determinar factores de riesgo sociodemográficos, antropométricos, bioquímico-metabólicos, clínicos y comorbilidades asociadas a fibrosis avanzada por enfermedad hepática esteatósica asociada a disfunción metabólica en pacientes con diabetes mellitus tipo 2. Estudio de casos y controles. Se revisaron 174 historias clínicas de pacientes con enfermedad hepática esteatósica asociada a disfunción metabólica y diabetes mellitus tipo 2 atendidos en el Hospital Nacional Dos de Mayo de 2009 a 2018. Los casos fueron pacientes con fibrosis avanzada y los controles sin fibrosis. La presencia de fibrosis avanzada fue definida por paneles clínicos predictores y/o resultado de biopsia hepática. Para determinar asociación se calculó odds ratio, chi cuadrado de Pearson y análisis de regresión logística. Se encontró asociación con edad > 60 años, un índice de masa corporal ≥ 25 kg/m2 , perímetro abdominal en varones ≥ 94 cm y perímetro abdominal ≥ 88 cm en mujeres, tiempo de enfermedad de diabetes > 10 años; complicaciones crónicas microvasculares; HDL en mujeres 60 años, índice de masa corporal elevado, perímetro abdominal en mujeres, HDL bajo en mujeres, complicaciones crónicas microvasculares e hipertensión. Se encontraron como factores de riesgo de fibrosis avanzada, edad mayor a 60 años, índice de masa corporal elevado, perímetro abdominal ≥ 88 cm en mujeres, complicaciones crónicas microvasculares, nivel bajo de HDL en mujeres e hipertensión arterial como principal comorbilidad.

To determine sociodemographic, anthropometric, biochemical-metabolic, clinical risk factors and comorbidities associated with advanced fibrosis due metabolic dysfunction associated steatotic liver disease in patients with diabetes mellitus type 2. Case-control study. We reviewed 174 medical records of patients with metabolic dysfunction associated steatotic liver disease and type 2 diabetes mellitus treated at the Hospital Nacional Dos de Mayo from 2009 to 2018. The cases were patients with advanced fibrosis and controls without fibrosis. The presence of advanced fibrosis was defined by predictive clinical panels and/or liver biopsy result. To determine association, odds ratio, Pearson's chi-square and logistic regression analysis were calculated. An association was found with age > 60 years, a body mass index ≥ 25 kg/m2 , abdominal circumference in men ≥ 94 cm and abdominal circumference ≥ 88 cm in women, time of diabetes disease >10 years; chronic microvascular complications; HDL in women 60 years, high body mass index, abdominal circumference in women, low HDL in women, chronic microvascular complications and hypertension remained independent risk factors. The risk factors for advanced fibrosis were age over 60 years, high body mass index, abdominal circumference ≥ 88 cm in women, chronic microvascular complications, low HDL level in women and hypertension as the main comorbidity.

Valor pronóstico de la fibrosis hepática valorada por el índice FIB4 en pacientes ingresados por síndrome coronario agudo / Prognostic value of liver fibrosis assessed by the FIB-4 index in patients with acute coronary syndrome

Introducción y objetivos: La fibrosis hepática precede a la cirrosis y a la insuficiencia hepática. Las formas subclínicas de fibrosis hepática podrían aumentar el riesgo de eventos cardiovasculares. El objetivo fue describir el valor pronóstico del índice FIB-4 en pacientes con síndrome coronario agudo (SCA) sobre la mortalidad hospitalaria y el pronóstico posterior. Métodos: Estudio retrospectivo de pacientes con SCA en un centro. Los objetivos de análisis fueron la mortalidad en la fase hospitalaria y tras el alta, así como la insuficiencia cardiaca y el sangrado mayor (SM), que se evaluaron tomando como evento competitivo la mortalidad por todas las causas y se presentan los sub-hazard ratios (sHR). Los eventos recurrentes se evaluaron mediante la razón de tasas de incidencia (IRR). Resultados: Se incluyeron a 3.106 pacientes y el 6,66% tenía un índice FIB-4 ≥ 1,3. El análisis multivariado verificó mayor riesgo de mortalidad intrahospitalaria asociado al índice FIB-4 (OR = 1,24; p=0,016) y los pacientes con valores> 2,67 presentaron el doble de riesgo (OR = 2,35; p=0,038). Tras el alta (mediana de seguimiento 1.112 días) el índice FIB-4 no tuvo valor pronóstico de mortalidad pero valores ≥ 1,3 se asociaron a mayor riesgo del primer reingreso (Shr = 1,61; p=0,04) o recurrente (IRR =1,70; p=0,001) de IC. El índice FIB-4 ≥ 1,30 se asoció con mayor riesgo de SM (sHR = 1,62; p=0,030). Conclusiones: La evaluación de la fibrosis hepática por el índice FIB-4 identifica a los pacientes con SCA con mayor riesgo de mortalidad intrahospitalaria pero también con mayor riesgo de IC y SM tras el alta.(AU)

Introduction and objectives: Liver fibrosis is present in nonalcoholic liver disease (NAFLD) and both precede liver failure. Subclinical forms of liver fibrosis might increase the risk of cardiovascular events. The objective of this study was to describe the prognostic value of the FIB-4 index on in-hospital mortality and postdischarge outcomes in patients with acute coronary syndrome (ACS). Methods: Retrospective study including all consecutive patients admitted for ACS between 2009 and 2019. According to the FIB-4 index, patients were categorized as <1.30, 1.30-2.67 or> 2.67. Heart failure (HF) and major bleeding (MB) were assessed taking all-cause mortality as a competing event and subhazard ratios (sHR) are presented. Recurrent events were evaluated by the incidence rate ratio (IRR). Results: We included 3106 patients and 6.66% had a FIB-4 index ≥ 1.3. A multivariate analysis verified a higher risk of in-hospital mortality associated with the FIB-4 index (OR, 1.24; P=.016). Patients with a FIB-4 index> 2.67 had a 2-fold higher in-hospital mortality risk (OR, 2.35; P=.038). After discharge (median follow-up 1112 days), the FIB-4 index had no prognostic value for mortality. In contrast, patients with FIB-4 index ≥ 1.3 had a higher risk of first (sHR, 1.61; P=.04) or recurrent (IRR, 1.70; P=.001) HF readmission. Similarly, FIB-4 index ≥ 1.30 was associated with a higher MB risk (sHR, 1.62; P=.030). Conclusions : The assessment of liver fibrosis by the FIB-4 index identifies ACS patients not only at higher risk of in-hospital mortality but also at higher risk of HF and MB after discharge.(AU)

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.

Correlation of liver fibrosis quantification by morphometry using HepaScan with the analysis of liver biopsies. A pilot study.

BACKGROUND: The gold standard for determining the degree of liver fibrosis (LF) continues to be biopsy evaluation. There are morphometry techniques that allow LF to be quantified on histopathological studies. OBJECTIVE: To measure the correlation between LF histological evaluation and fibrosis percentage (FP) morphometric quantification using the HepaScan software. MATERIAL AND METHODS: Observational, analytical, cross-sectional, prospective, prolective pilot study in which liver histological sections from 29 people who died from some liver disease and from 22 people who died from other causes (controls) were analyzed. FP was calculated with HepaScan on digital photographs of histological sections stained with the Masson technique, comparing it with the diagnosis established by three expert pathologists. RESULTS: Four-hundred and one images from the group with liver disease and 250 from the control group were analyzed. Inter-observer agreement had a kappa index of 0.329. There were FP statistically significant differences (p = 0.0001) between histopathological classification groups. HepaScan predictive capacity based on the area under the receiver operating characteristic curve was 0.983, 0.812, and 0.895 for mild, moderate, and severe fibrosis, respectively. CONCLUSIONS: HepaScan showed very good performance for evaluating FP in histological sections, which is why it can contribute to qualitative pathological diagnosis.

ANTECEDENTES: El estándar de oro para determinar el grado de fibrosis hepática (FH) continúa siendo la evaluación de la biopsia. Existen técnicas de morfometría que permiten cuantificar la FH en estudios histopatológicos. OBJETIVO: Medir la correlación entre la evaluación histológica de FH y la cuantificación por morfometría del porcentaje de fibrosis (PF) mediante HepaScan. MATERIAL Y MÉTODOS: Estudio piloto observacional, analítico, transversal, prospectivo y prolectivo en el que se analizaron cortes histopatológicos de hígado de 29 personas fallecidas por alguna hepatopatía y 22 personas fallecidas por otras causas (controles). El PF se calculó con HepaScan en fotografías digitales de cortes histológicos teñidos con la técnica Masson, comparándolo con el diagnóstico de tres patólogos expertos. RESULTADOS: Fueron analizadas 401 imágenes del grupo con hepatopatía y 250 del grupo de control. La concordancia interobservador tuvo un índice kappa de 0.329. Entre los grupos de clasificación histopatológica existieron diferencias estadísticas en el PF (p = 0.0001). La capacidad predictiva de HepaScan con base en el área bajo la curva característica operativa del receptor fue de 0.983, 0.812 y 0.895 para fibrosis leve, moderada y severa, respectivamente. CONCLUSIONES: HepaScan mostró muy buen desempeño para evaluar el PF en cortes histológicos, por lo que puede coadyuvar al diagnóstico patológico cualitativo.

Correlación de la cuantificación de fibrosis hepática por morfometría mediante HepaScan con el análisis de las biopsias hepáticas. Estudio piloto / Correlation of liver fibrosis quantification by morphometry using HepaScan with the analysis of liver biopsies. A pilot study

Resumen Antecedentes: El estándar de oro para determinar el grado de fibrosis hepática (FH) continúa siendo la evaluación de la biopsia. Existen técnicas de morfometría que permiten cuantificar la FH en estudios histopatológicos. Objetivo: Medir la correlación entre la evaluación histológica de FH y la cuantificación por morfometría del porcentaje de fibrosis (PF) mediante HepaScan. Material y métodos: Estudio piloto observacional, analítico, transversal, prospectivo y prolectivo en el que se analizaron cortes histopatológicos de hígado de 29 personas fallecidas por alguna hepatopatía y 22 personas fallecidas por otras causas (controles). El PF se calculó con HepaScan en fotografías digitales de cortes histológicos teñidos con la técnica Masson, comparándolo con el diagnóstico de tres patólogos expertos. Resultados: Fueron analizadas 401 imágenes del grupo con hepatopatía y 250 del grupo de control. La concordancia interobservador tuvo un índice kappa de 0.329. Entre los grupos de clasificación histopatológica existieron diferencias estadísticas en el PF (p = 0.0001). La capacidad predictiva de HepaScan con base en el área bajo la curva característica operativa del receptor fue de 0.983, 0.812 y 0.895 para fibrosis leve, moderada y severa, respectivamente. Conclusiones: HepaScan mostró muy buen desempeño para evaluar el PF en cortes histológicos, por lo que puede coadyuvar al diagnóstico patológico cualitativo.

Abstract Background: The gold standard for determining the degree of liver fibrosis (LF) continues to be biopsy evaluation. There are morphometry techniques that allow LF to be quantified on histopathological studies. Objective: To measure the correlation between LF histological evaluation and fibrosis percentage (FP) morphometric quantification using the HepaScan software. Material and methods: Observational, analytical, cross-sectional, prospective, prolective pilot study in which liver histological sections from 29 people who died from some liver disease and from 22 people who died from other causes (controls) were analyzed. FP was calculated with HepaScan on digital photographs of histological sections stained with the Masson technique, comparing it with the diagnosis established by three expert pathologists. Results: Four-hundred and one images from the group with liver disease and 250 from the control group were analyzed. Inter-observer agreement had a kappa index of 0.329. There were FP statistically significant differences (p = 0.0001) between histopathological classification groups. HepaScan predictive capacity based on the area under the receiver operating characteristic curve was 0.983, 0.812, and 0.895 for mild, moderate, and severe fibrosis, respectively. Conclusions: HepaScan showed very good performance for evaluating FP in histological sections, which is why it can contribute to qualitative pathological diagnosis.

Prognostic value of liver fibrosis assessed by the FIB-4 index in patients with acute coronary syndrome.

INTRODUCTION AND OBJECTIVES: Liver fibrosis is present in nonalcoholic liver disease (NAFLD) and both precede liver failure. Subclinical forms of liver fibrosis might increase the risk of cardiovascular events. The objective of this study was to describe the prognostic value of the FIB-4 index on in-hospital mortality and postdischarge outcomes in patients with acute coronary syndrome (ACS). METHODS: Retrospective study including all consecutive patients admitted for ACS between 2009 and 2019. According to the FIB-4 index, patients were categorized as <1.30, 1.30-2.67 or> 2.67. Heart failure (HF) and major bleeding (MB) were assessed taking all-cause mortality as a competing event and subhazard ratios (sHR) are presented. Recurrent events were evaluated by the incidence rate ratio (IRR). RESULTS: We included 3106 patients and 6.66% had a FIB-4 index ≥ 1.3. A multivariate analysis verified a higher risk of in-hospital mortality associated with the FIB-4 index (OR, 1.24; P=.016). Patients with a FIB-4 index> 2.67 had a 2-fold higher in-hospital mortality risk (OR, 2.35; P=.038). After discharge (median follow-up 1112 days), the FIB-4 index had no prognostic value for mortality. In contrast, patients with FIB-4 index ≥ 1.3 had a higher risk of first (sHR, 1.61; P=.04) or recurrent (IRR, 1.70; P=.001) HF readmission. Similarly, FIB-4 index ≥ 1.30 was associated with a higher MB risk (sHR, 1.62; P=.030). CONCLUSIONS: The assessment of liver fibrosis by the FIB-4 index identifies ACS patients not only at higher risk of in-hospital mortality but also at higher risk of HF and MB after discharge.

NAFLD and type 2 diabetes: A practical guide for the joint management.

Non-alcoholic fatty liver disease (NAFLD) is becoming a major cause of liver disease-related morbidity, as well as mortality. Importantly, NAFLD is considered a mediator of systemic diseases including cardiovascular disease. Its prevalence is expected to increase, mainly due to its close association with obesity and type 2 diabetes mellitus (T2D). In addition, T2D and NAFLD share common pathophysiological mechanisms, and one can lead to or worsen the other. Therefore, a close collaboration between primary care physician, endocrinologists and hepatologists is essential to optimize the management of patients with NAFLD and T2D. Here, we summarize relevant aspects about NAFLD and T2D that all clinician managing these patients should know as well as current therapeutic options for the treatment of T2D associated with NAFLD.

Prediction of clinical events by liver stiffness and chronic kidney disease by NAFLD in patients with type-2 diabetes.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with poorer glycemic control and a higher risk of type-2 diabetes (T2D) complications, extrahepatic and cardiovascular disease (CVD). Our study aim was to evaluate the association between NAFLD, T2D complications, and the development of overall clinical events (OCE) (CV, liver-related, and mortality) in patients with T2D. METHODS: Prospective single-center study comprising T2D subjects with no history of CVD and non-T2D matched controls. Patients were selected from the Outpatient Diabetes Clinic of Vall d'Hebron Hospital and related primary care centers. RESULTS: 186 diabetics and 57 controls were included. Amongst T2D, 124/186 subjects had NAFLD (66.6%). T2D-NAFLD subjects showed a heavier metabolic burden and higher median liver stiffness (5.6kPa [4.5-7.3] vs 4.8 [4.2-5.8]; p=0.004) compared to non-NAFLD diabetics. During a median follow-up of 5.6 years, 33 (17.7%) T2D patients developed OCE vs 4 (7.0%) controls (p=0.049). No differences were found for OCE between NAFLD and non-NAFLD diabetics (16.9% vs 19.4%; p=0.68). CV was the most reported outcome and only one liver event occurred. NAFLD diabetics showed more often chronic kidney disease (CKD), whereas T2D complications and subclinical CVD rates were similar. A higher liver stiffness, older age, and male gender were independently associated with OCE amongst the entire T2D population and NAFLD diabetics. CONCLUSIONS: NAFLD and liver stiffness were associated with CKD and clinical outcomes in diabetics, respectively. A hepatic evaluation is recommended to identify high-risk T2D patients that would benefit from early referral to specialized care.

Esteatohepatitis no alcohólica / Non-alcoholic steatohepatitis

La esteatohepatitis no alcohólica forma parte del espectro de la esteatosis hepática metabólica (EHmet), que se caracteriza por la presencia de esteatosis hepática en pacientes con disfunción metabólica o inmunomediada asociada a obesidad, diabetes, síndrome metabólico, dislipidemia y enfermedades inmunomediadas. La EHmet es una enfermedad prevalente, heterogénea, compleja y dinámica. Es paucisintomática, manifestada por astenia y prurito que afecta la calidad de vida relacionada con la salud. El diagnóstico se realiza por métodos no invasivos bioquímicos o de imagen (ecografía y resonancia magnética) y biopsia hepática. Su tratamiento se basa en intervención en estilo de vida promoviendo dieta mediterránea hipocalórica con el objetivo de perder peso, ejercicio físico para combatir la sarcopenia, así como abstinencia completa de consumir alcohol; en caso de no respuesta se utilizarán fármacos para promover la regresión de la esteatosis, la inflamación y la fibrosis. (AU)

Non-alcoholic steatohepatitis belongs to the spectrum of metabolic-associated fatty liver diseases characterized by steatosis linked to obesity, diabetes, metabolic syndrome, dyslipidemia and immune-mediated disorders. The main features of MAFLD include high prevalence, heterogeneity, complexity and dynamic disease. Pruritus and asthenia are the main clinical manifestation that impact on quality of life and patient-reported outcomes. Biochemical or imagen-based non-invasive test have been implemented in the diagnostic process. Liver biopsy remains as the gold standard. Therapeutic options included life-style intervention. Mediterranean hypocaloric Diet to lose weight, exercise to fight sarcopenia and alcohol abstinence. In non-responders, drug-therapy focusing on obesity, diabetes and fibrosis using sequentially or combined to promote steatosis, inflammation and fibrosis regression. (AU)

Prevalence of non-alcoholic fatty liver disease (NAFLD) in a cohort of patients with type 2 diabetes: the PHIGNA-DM2 study.

Introduction: Background: type 2 diabetes (T2D) is a risk factor for nonalcoholic fatty liver disease (NAFLD). Objective: to evaluate the prevalence of NAFLD in a cohort of patients with T2D. Methods: an observational, descriptive study performed between May 2018 and December 2019 at the Endocrinology and Nutrition Unit. The χ² test was performed for qualitative variables and a non-parametric test for the comparison of medians of quantitative variables. Steatosis degree was defined by the coefficient attenuated parameter (CAP): (S0: < 248 dB/m; S1: 248-268 dB/m; S2: 268-288 dB/m; S3: > 288 dB/m) or stiffness: F0-F1: < 8 kPa; F2: 8-10 kPa; F3: 10-15 kPa; F4: > 15 kPa, using transient elastography (TE) (FibroScan®). A univariate analysis was performed and subsequently a multivariate analysis with statistically significant variables used to study the predictive factors of intense steatosis and advanced fibrosis. Results: n = 104 patients with T2D; 84 (80.7 %) were obese. TE demonstrated advanced fibrosis in 20 % and intense steatosis (S3) in more than 50 %. Lower total bilirubin (OR: 0.028; 95 % CI: (0.002-0.337); p = 0.005) was found to be an independent factor for S3 steatosis in the multivariate analysis. BMI ((OR: 1.497; 95 % CI: (1.102-2.034); p = 0.01)) was a predictive factor for advanced fibrosis in a multivariate analysis. Conclusions: NAFLD-associated intense steatosis and NAFLD-associated fibrosis were commonly found in patients with T2DM and obesity. Diabetic patients should be screened for liver disease as one more target organ.

Introducción: Antecedentes: la diabetes de tipo 2 (DM2) es un factor de riesgo para la enfermedad del hígado graso no alcohólico (EHGNA). Objetivo: evaluar la prevalencia de la EHGNA en una cohorte de pacientes con DM2. Métodos: estudio descriptivo observacional realizado entre mayo de 2018 y diciembre de 2019 en la Unidad de Endocrinología y Nutrición. Se realizó una prueba de χ² para las variables cualitativas y una prueba no paramétrica para la comparación de medianas de variables cuantitativas. El grado de esteatosis se definió mediante el parámetro coeficiente atenuado (CAP): (S0: < 248 dB/m; S1: 248-288 dB/m; S2: 268-288 dB/m; S3: > 288 dB/m) o rigidez: F0-F1: < 8 kPa; F2: 8-10 kPa; F3: 10-15 kPa; F4: > 15 kPa, usando la elastografía transitoria (TE) (FibroScan®). Se realizó un análisis univariante y posteriormente un análisis multivariante con las variables estadísticamente significativas para estudiar los factores predictivos de esteatosis intensa y fibrosis avanzada. Resultados: n = 104 pacientes con DM2; 84 (80,7 %) eran obesos. La TE demostró fibrosis avanzada en el 20 % y esteatosis intensa (S3) en más del 50 %. Los niveles disminuidos de bilirrubina total (OR: 0.028; 95 % CI: (0.002-0.337); p = 0.005) se encontraron como factores independientes para la esteatosis S3 en el analisis multivariable. El IMC (OR: 1.497; 95 % CI: (1.102-2.034); p = 0.01) fue un factor predictivo de fibrosis avanzada. Conclusiones: la esteatosis intensa asociada a EHGNA y la fibrosis asociada a EHGNA se encontraron comúnmente en pacientes con DM2 y obesidad. Los pacientes diabéticos deben someterse a pruebas de detección de enfermedad hepática como un órgano diana más.