Utility of Transient Elastography for the Screening of Liver Disease in Patients with Alpha1-Antitrypsin Deficiency

Deficiència d'alfa1-antitripsina; Malaltia del fetge; Elastografia transitòriaAlpha1-antitrypsin deficiency; Liver disease; Transient elastographyDeficiencia de alfa1-antitripsina; Enfermedad del hígado; Elastografía transitoriaScreening of liver disease in alpha-1 antitrypsin deficiency (AATD) is usually carried out with liver enzymes, with low sensitivity. We conducted a multicenter cross-sectional study aiming to describe the utility of transient elastography for the identification of liver disease in patients with AATD. A total of 148 AATD patients were included. Among these, 54.7% were Pi*ZZ and 45.3% were heterozygous for the Z allele. Between 4.9% and 16.5% of patients had abnormal liver enzymes, without differences among genotypes. Liver stiffness measurement (LSM) was significantly higher in Pi*ZZ individuals than in heterozygous Z (5.6 vs. 4.6 kPa; p = 0.001). In total, in 8 (5%) individuals LSM was >7.5 kPa, considered significant liver fibrosis, and ≥10 kPa in 3 (1.9%) all being Pi*ZZ. Elevated liver enzymes were more frequently observed in patients with LSM > 7.5 kPa, but in 5 out of 8 of these patients all liver enzymes were within normal range. In patients with AATD, the presence of abnormal liver enzymes is frequent; however, most of these patients do not present significant liver fibrosis. Transient elastography can help to identify patients with liver fibrosis even with normal liver enzymes and should be performed in all Z-allele carriers to screen for liver disease.This research was funded by Grifols through an unrestricted grant from the Catalan Center for Research in Alpha-1 antitrypsin deficiency of the Vall d’Hebron Research Institute (VHIR) in the Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; from the Madrid Center for Research in Alpha-1 antitrypsin deficiency of the Hospital Clínico San Carlos, Madrid, Spain; from the Galicia Center for Research in Alpha-1 antitrypsin deficiency of the University Hospital Complex of Vigo, Spain; as well as a research grant from Fundació Catalana de Pneumologia (FUCAP)

Variables psicológicas implicadas en la actitud e iniciativa emprendedora

Identificar variables individuales relacionadas con la iniciativa emprendedora y el fomento de competencias transversales relacionadas con la misma, supone un desafío en la investigación actual sobre emprendimiento. El proyecto titulado Variables psicológicas implicadas en la actitud e iniciativa emprendedora, realizado bajo el programa Innova Docencia promovido por el Vicerrectorado de Calidad de la UCM en la convocatoria 2016-2017, ha tenido por objetivo analizar y evaluar variables psicológicas relacionadas con emprendimiento que presentan una muestra de estudiantes de la Universidad Complutense de Madrid. En dicho estudio han participado 1222 estudiantes de la UCM correspondientes a 27 titulaciones: 14 de Grado, 2 de Dobles Grados, y 11 de Máster. El 28,6% de la muestra fueron hombres y el 71% fueron mujeres. La media de edad fue de 20,43 años. El equipo investigador estuvo compuesto por 40 personas: 25 PDI de la UCM, 2 PAS, 8 alumnos y alumnas, 1 técnico, y 4 PDI de las universidades de Castilla-La Mancha (UCLM), UNED, Carlos III de Madrid (UC3M), y Alcalá de Henares (UAH). El PDI de la UCM correspondía a las siguientes facultades: Psicología (7), Ciencias de la Documentación (3), Ciencias Económicas y Empresariales (6), Ciencias Políticas y Sociología (3), Comercio (1), Trabajo Social (1), Ciencias Biológicas (2), Informática (1), y Bellas Artes (1). Un equipo UCM perteneciente a 9 facultades, que representó a 13 departamentos y a todas las áreas de conocimiento. La metodología empleada consistió en un cuestionario que evaluaba los siguientes aspectos: datos sociodemográficos, actitud emprendedora, y las variables psicológicas: personalidad, inteligencia emocional, resolución de problemas y tolerancia a la ambigüedad. Se optó por instrumentos estandarizados, con buenas características psicométricas de fiabilidad y validez que permitieran obtener resultados robustos, con amplia evidencia empírica y que evaluaban adecuadamente variables que la literatura ha relacionado con la actitud e iniciativa emprendedora. Además todos ellos se han utilizado en investigaciones relacionadas con emprendimiento, lo que aumentó la validez externa. Se ha analizado la iniciativa emprendedora desde el punto de vista de los estudiantes y también teniendo en cuenta variables del entorno familiar y personal. Los resultados nos muestran que son las variables psicológicas de extraversión, reparación emocional y estrategias de resolución de problemas las que predicen la iniciativa emprendedora. Los estudiante que compaginan estudios y trabajo tienen una mayor iniciativa emprendedora, y aquellos cuyos padres y/o pareja desarrollan su actividad laboral como autónomos. Se presentan datos por titulación académica, sexo, actividad laboral de los padres y compaginar estudios y trabajo. Se muestran datos de todas las variables psicológicas por titulación académica, y una comparativa de dichas variables entre los universitarios, un grupo de estudiantes de Formación Profesional (FP) y una muestra de emprendedores reales. Los resultados obtenidos son relevantes para tomar decisiones orientadas a la mejora de la actitud, iniciativa y comportamiento emprendedor. Permitirán el diseño y ejecución de actividades académicas para sensibilizar a los estudiantes en la cultura emprendedora, y formar en competencias transversales, cada vez más demandadas, para mejorar la empleabilidad y competitividad como claves para el crecimiento de nuestra sociedad

STK25- a new key regulator of metabolic profile and a possible target for anti-diabetic drug

Type 2 diabetes (T2D) affects at least 285 million people worldwide and its prevalence is rapidly increasing. Understanding the molecular mechanisms controlling ectopic lipid deposition and insulin response in metabolic tissues is essential for developing new pharmacological strategies to effectively treat T2D. Obesity and overweigh are the main risk factors for developing T2D, but nonalcoholic fatty liver disease (NAFLD) also contributes to the pathogenesis of T2D. Today, achieving good glycemic control in T2D patients with the current treatment alternatives remains challenging and no specific therapy exists against NAFLD. In this thesis, we describe protein kinase STK25 as a new key regulator of ectopic lipid deposition in skeletal muscle, liver and pancreas as well as whole-body metabolism. We have found that STK25 overexpression in mice challenged with a high-fat diet (HFD) results in an increased ectopic lipid deposition in skeletal muscle and pancreas, accompanied by an aggravated fibrosis and inflammation. The overexpression of STK25 also leads to impairments in β-oxidation and decrease in in vivo insulin-stimulated glucose uptake in skeletal muscle and reduced endurance exercise capacity in mice. The pancreas of Stk25 transgenic animals shows a significant decrease in islet β/α-cell ratio and alterations in the islet architecture with an increased presence of α-cells within the islet core, together with an impaired insulin production during IPGTT after a HFD challenge. We also show that treatment with Stk25 antisense oligonucleotides in obese mice protects against HFD-induced liver steatosis, glucose intolerance and insulin resistance. In addition, we found a significant positive correlation between nonalcoholic steatohepatitis (NASH) development and STK25 protein abundance in human liver biopsies. Furthermore, we have identified four common non-linked SNPs in the human STK25 gene that are associated with altered liver fat: two associated with increased hepatic fat levels and two associated with decreased levels. Taken together, our studies suggest that pharmacological inhibition of STK25 potentially provides a new-in-class therapeutic strategy for the treatment of NAFLD, T2D and related metabolic complications

Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver DiseaseSummary

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide. Currently, no specific pharmacologic therapy is available for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the 21st century. Our recent studies in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine protein kinase (STK)25 as a critical regulator of hepatic lipid partitioning and NAFLD/NASH. Here, we studied the metabolic benefit of liver-specific STK25 inhibitors on NAFLD development and progression in a mouse model of diet-induced obesity. Methods: We developed a hepatocyte-specific triantennary N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide (ASO) targeting Stk25 and evaluated its effect on NAFLD features in mice after chronic exposure to dietary lipids. Results: We found that systemic administration of hepatocyte-targeting GalNAc-Stk25 ASO in obese mice effectively ameliorated steatosis, inflammatory infiltration, hepatic stellate cell activation, nutritional fibrosis, and hepatocellular damage in the liver compared with mice treated with GalNAc-conjugated nontargeting ASO, without any systemic toxicity or local tolerability concerns. We also observed protection against high-fat-diet–induced hepatic oxidative stress and improved mitochondrial function with Stk25 ASO treatment in mice. Moreover, GalNAc-Stk25 ASO suppressed lipogenic gene expression and acetyl-CoA carboxylase protein abundance in the liver, providing insight into the molecular mechanisms underlying repression of hepatic steatosis. Conclusions: This study provides in vivo nonclinical proof-of-principle for the metabolic benefit of liver-specific inhibition of STK25 in the context of obesity and warrants future investigations to address the therapeutic potential of GalNAc-Stk25 ASO in the prevention and treatment of NAFLD. Keywords: NAFLD, NASH, Hepatic Steatosis, Liver Fibrosis, Antisense Oligonucleotide Therap

The Importance of Reference Centers and Registries for Rare Diseases: The Example of Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency (AATD) is a rare and underdiagnosed disease that is associated with the development of liver disease in adults and children and pulmonary emphysema in adults. Several studies have shown that there is limited knowledge about the disease and its diagnosis among health care providers, and there is an important inequity in the access to specialized care and appropriate treatment across Europe. The European Commision and the European Respiratory Society (ERS) recommend that the care of patients with AATD must be organized in reference centers at national or regional levels. These reference centers must provide optimal clinical care in terms of adequate diagnostic techniques, such as phenotyping and genotyping, and ensure access to treatment according to guidelines. Reference centers should also provide continuous medical education for health care professionals, genetic counseling, collaboration with patient associations and promote collaborative research and clinical trials with new and existing treatments for the disease. These centers must have a registry of their activity and collaborate with large, international, multicenter registries, such as the European Alpha-1 antitrypsin Deficiency Research Collaboration (EARCO) international registry, which is endorsed by the ERS, and aims to recruit up to 3,000 patients over a period of three years and prospectively follow them to better understand the natural history of the disease and the impact of different treatments on outcomes in a real life setting. International collaboration and standardized collection of high-quality prospective data will provide new insights into the clinical manifestations and prognosis of AATD.Alexa Núñez is the recipient of a Rio Hortega contract in the 2019 Strategic Action Health Call from the Instituto de Salud Carlos III for the years 2020-2022. Miriam Barrecheguren is the recipient of a Rio Hortega contract in the 2017 Strategic Action Health Call from the Instituto de Salud Carlos III for the years 2018-2019. The Spanish centers for Alpha-1 antitrypsin Deficiency are funded by unrestricted research grants from Grifols

Utility of transient elastography for screening of liver disease in patients with alpha1-antitrypsin deficiency.

Screening of liver disease in alpha-1 antitrypsin deficiency (AATD) is usually carried out with liver enzymes, with low sensitivity. We conducted a multicenter cross-sectional study aiming to describe the utility of transient elastography for the identification of liver disease in patients with AATD. A total of 148 AATD patients were included. Among these, 54.7% were Pi*ZZ and 45.3% were heterozygous for the Z allele. Between 4.9% and 16.5% of patients had abnormal liver enzymes, without differences among genotypes. Liver stiffness measurement (LSM) was significantly higher in Pi*ZZ individuals than in heterozygous Z (5.6 vs. 4.6 kPa; p = 0.001). In total, in 8 (5%) individuals LSM was >7.5 kPa, considered significant liver fibrosis, and ≥10 kPa in 3 (1.9%) all being Pi*ZZ. Elevated liver enzymes were more frequently observed in patients with LSM > 7.5 kPa, but in 5 out of 8 of these patients all liver enzymes were within normal range. In patients with AATD, the presence of abnormal liver enzymes is frequent; however, most of these patients do not present significant liver fibrosis. Transient elastography can help to identify patients with liver fibrosis even with normal liver enzymes and should be performed in all Z-allele carriers to screen for liver disease

Genetic Disruption of Protein Kinase STK25 Ameliorates Metabolic Defects in a Diet-Induced Type 2 Diabetes Model

Understanding the molecular networks controlling ectopic lipid deposition, glucose tolerance, and insulin sensitivity is essential to identifying new pharmacological approaches to treat type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a negative regulator of glucose and insulin homeostasis based on observations in myoblasts with acute depletion of STK25 and in STK25-overexpressing transgenic mice. Here, we challenged Stk25 knockout mice and wild-type littermates with a high-fat diet and showed that STK25 deficiency suppressed development of hyperglycemia and hyperinsulinemia, improved systemic glucose tolerance, reduced hepatic gluconeogenesis, and increased insulin sensitivity. Stk25(−/−) mice were protected from diet-induced liver steatosis accompanied by decreased protein levels of acetyl-CoA carboxylase, a key regulator of both lipid oxidation and synthesis. Lipid accumulation in Stk25(−/−) skeletal muscle was reduced, and expression of enzymes controlling the muscle oxidative capacity (Cpt1, Acox1, Cs, Cycs, Ucp3) and glucose metabolism (Glut1, Glut4, Hk2) was increased. These data are consistent with our previous study of STK25 knockdown in myoblasts and reciprocal to the metabolic phenotype of Stk25 transgenic mice, reinforcing the validity of the results. The findings suggest that STK25 deficiency protects against the metabolic consequences of chronic exposure to dietary lipids and highlight the potential of STK25 antagonists for the treatment of type 2 diabetes