Metabolic alterations, HFE gene mutations and atherogenic lipoprotein modifications in patients with primary iron overload

Abstract Iron overload (IO) has been associated with glucose metabolism alterations and increased risk of cardiovascular disease (CVD). Primary IO is associated with mutations in the HFE gene. To which extent HFE gene mutations and metabolic alterations contribute to the presence of atherogenic lipoprotein modifications in primary IO remains undetermined. The present study aimed to assess small, dense low-density lipoprotein (LDL) levels, chemical composition of LDL and high-density lipoprotein (HDL) particles, and HDL functionality in IO patients. Eighteen male patients with primary IO and 16 sex-and age-matched controls were recruited. HFE mutations (C282Y, H63D and S65C), measures of insulin sensitivity and secretion (calculated from the oral glucose tolerance test), chemical composition and distribution profile of LDL and HDL subfractions (isolated by gradient density ultracentrifugation) and HDL functionality (as cholesterol efflux and antioxidative activity) were studied. IO patients compared with controls exhibited insulin resistance (HOMA-IR (homoeostasis model assessment-estimated insulin resistance): +93 %, P < 0.001). Metabolic profiles differed across HFE genotypes. C282Y homozygotes (n = 7) presented a reduced β-cell function and insulin secretion compared with non-C282Y patients (n = 11) (−58 % and −73 %, respectively, P < 0.05). In addition, C282Y homozygotes featured a predominance of large, buoyant LDL particles (C282Y: 43 + − 5; non-C282Y: 25 + − 8; controls: 32 + − 7 %; P < 0.001), whereas non-C282Y patients presented higher amounts of small, dense LDL (C282Y: 23 + − 5; non-C282Y: 39 + − 10; controls: 26 + − 4 %; P < 0.01). HDL particles were altered in C282Y homozygotes. However, HDL functionality was conserved. In conclusion, metabolic alterations and HFE gene mutations are involved in the presence of atherogenic lipoprotein modifications in primary IO. To what extent such alterations could account for an increase in CVD risk remains to be determined

Diagnosis and treatment of non-alcoholic fatty liver disease: Argentine Association for the Study of Liver Diseases, year 2019

El hígado graso no alcohólico (HGNA) es la enfermedad hepática crónica más frecuente en todo el mundo, con una prevalencia aproximada de 25% a nivel global. Su prevalencia es mucho mayor en pacientes con sobrepeso, obesidad y diabetes tipo 2 y es considerada como la manifestación hepática del síndrome metabólico. El espectro de la enfermedad hepática es muy amplio, desde la esteatosis simple a la esteatohepatitis, fibrosis, cirrosis y sus complicaciones, como el hepatocarcinoma. La mayoría de los pacientes afectados no progresará a la fibrosis avanzada/cirrosis. A pesar de esto, se ha descripto que la hepatopatía es la tercera causa de muerte entre los pacientes con HGNA, luego de las enfermedades cardiovasculares y las malignas. Entre la enorme cantidad de afectados, lo más importante es identificar a los que están en riesgo de evolución a la cirrosis o sus complicaciones y conocer las opciones de diagnóstico y tratamiento. En esta Guía organizada por la Asociación Argentina para el Estudio de las Enfermedades del Hígado se revisan las definiciones, los aspectos epidemiológicos, la historia natural y un enfoque práctico sobre algoritmos posibles para estimar la gravedad de la hepatopatía en cada caso, además de analizar los avances en el tratamiento y recomendaciones para el seguimiento. Es importante señalar que no se han publicado datos sobre incidencia o prevalencia de la enfermedad en población general de Argentina, y se alienta a la realización de los mismos.. Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease worldwide, with an estimated global prevalence of approximately 25%, that is much higher in patients with overweight, obesity and type 2 diabetes. NAFLD is considered as the hepatic manifestation of metabolic syndrome. It has a wide spectrum, from simple steatosis to steatohepatitis, fibrosis, cirrhosis and its complications, such as hepatocellular carcinoma. Most of the affected patients will not evolve to advanced fibrosis or cirrhosis. Despite this, it has been described that the hepatic disease is the third cause of death among patients with nonalcoholic fatty liver, after cardiovascular and malignant diseases. Among the huge number of patients affected, the main challenge is to identify those who are at risk of developing cirrhosis or its complications and to recognize the diagnostic and treatment options. In this Guideline, endorsed by the Argentine Association for the Study of Liver Diseases, the definitions, epidemiological aspects, natural history and a practical approach to possible algorithms to estimate the severity of liver disease in the individual patient are reviewed; in addition to analyzing advances in treatment and proposing recommendations for follow-up. It is important to note that no data on the incidence or prevalence of the disease have been published in the general population of Argentina, and it is encouraged to carry them out.Fil: Fassio, Eduardo. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Dirchwolf, Melisa. Hospital Privado de Rosario; ArgentinaFil: Barreyro, Fernando Javier. Universidad Nacional de Misiones. Facultad de Ciencias Exactas, Químicas y Naturales. Departamento de Microbiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Adrover, Raúl. No especifíca;Fil: Alonso, M. Inés. No especifíca;Fil: Amante, Marcelo. No especifíca;Fil: Ameigeiras, Beatriz. No especifíca;Fil: Barreyro, Fernando J.. No especifíca;Fil: Benavides, Javier. No especifíca;Fil: Bessone, Fernando. No especifíca;Fil: Cairo, Fernando. No especifíca;Fil: Camino, Alejandra. No especifíca;Fil: Cañero Velasco, M. Cristina. No especifíca;Fil: Casciato, Paola. No especifíca;Fil: Cocozzella, Daniel. No especifíca;Fil: Daruich, Jorge. No especifíca;Fil: De Matteo, Elena. No especifíca;Fil: Dirchwolf, Melisa. No especifíca;Fil: Fassio, Eduardo. No especifíca;Fil: Fernández, José Luis. No especifíca;Fil: Fernández, Nora. No especifíca;Fil: Ferretti, Sebastián. No especifíca;Fil: Figueroa, Sebastián. No especifíca;Fil: Galoppo, Marcela. No especifíca;Fil: Godoy, Alicia. No especifíca;Fil: González Ballerga, Esteban. No especifíca;Fil: Graffigna, Mabel. No especifíca;Fil: Guma, Carlos. No especifíca;Fil: Lagues, Cecilia. No especifíca;Fil: Marino, Mónica. No especifíca;Fil: Mendizábal, Manuel. No especifíca;Fil: Mesquida, Marcelo. No especifíca;Fil: Odzak, Andrea. No especifíca;Fil: Peralta, Mirta. No especifíca;Fil: Ridruejo, Ezequiel. No especifíca;Fil: Ruffillo, Gabriela. No especifíca;Fil: Sordá, Juan A.. No especifíca;Fil: Tanno, Mario. No especifíca;Fil: Villamil, Alejandra. No especifíca;Fil: Colombato, Luis. No especifíca;Fil: Fainboim, Hugo. No especifíca;Fil: Gadano, Adrián. No especifíca;Fil: Galoppo, Cristina. No especifíca;Fil: Villamil, Federico. No especifíca

Tratamiento en pacientes con transaminasas normales

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Editorial: bezafibrate in the treatment of patients with primary biliary cholangitis—are we there yet? Authors' reply

We thank Drs Rodrigues and Banales for the interest in our study.1, 2 We aimed to examine the histological effect of the combination of ursodeoxycholic acid (UDCA) and bezafibrate (BZF) in difficult to treat patients with primary biliary cholangitis (PBC). We agree with Dr Rodrigues et al that late-stage PBC is an entity underrepresented in clinical trials, so recruitment of greater number of patients with the cirrhotic disease may be difficult to obtain in future trials. PBC is increasingly diagnosed at a much earlier stage, and more than 60% of patients are asymptomatic at presentation with the majority not having cirrhosis3, 4; this was observed in our study. Thus a key therapeutic challenge in early non-cirrhotic PBC is to prevent progression; and/or if fibrosis exists to promote regression to earlier stages. The early identification of progression based on biomarkers and predictive scores is important for this group of difficult-to-treat patients with PBC who may benefit from therapies beyond UDCA, including obeticholic acid, off-label bezafibrate, as well as clinical trial agents in development.5Our results reinforced previous data on patients with PBC for whom UDCA response is insufficient, where combined UDCA-BZF therapy is associated with significant decreases or even normalization of biochemical markers of cholestasis.6 We observed that normalization of ALP at 12 months was associated with histological benefit at 5 years, but not in those patients without ALP normalization. Moreover, we observed a significant improvement in GLOBE and UK-PBC risk score under UDCA-BZF therapy. However, these results should be considered with caution since these predictive score needs to be validated in combination therapy; furthermore, the impact of BZF on AST values (a component of APRI and the UK-PBC risk score) needs better understanding, recognising extra-hepatic sources for the AST may include fibrate induced myopathy.We want to point out that moderate or severe lymphocytic interface hepatitis (LIH) has been identified as an independent predictive factor of cirrhosis development as well as liver-related morbidity and mortality.7, 8 Notably, LIH evaluation still needs liver biopsy since non-invasive biomarkers are not validated for this histologic finding. As for the POISE trial population where obeticholic acid was studied,9 we observed a high prevalence of LIH in our cohort, which was a marker of low probability of UDCA response.10 However, in our study, a significant reduction in LIH was associated with UDCA-BZF therapy.Finally, we agree with the editorial that the benefit of UDCA-BZF combination treatment needs further studies, especially in long-term controlled studies, in comparison with, and/or in conjunction with other therapies such as obeticholic acid, and from a cost-effectiveness perspective.Fil: Sorda, Juan Antonio. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: González Ballerga, Esteban. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Barreyro, Fernando Javier. Universidad Nacional de Misiones; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Daruich, Jorge. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentin

Alterations in triglyceride rich lipoproteins are related to endothelial dysfunction in metabolic syndrome

Our aim was to analyze the effect of circulating triglyceride rich lipoprotein (TRL) on endothelial function in metabolic syndrome (MetS). Methods We studied 40 patients with MetS (ATPIII), divided into those presenting normal endothelial function (n = 19) and those with endothelial dysfunction (n = 21) by means of the evaluation of pulse wave velocity, before and after brachial artery ischemia. In fasting serum we measured lipid and lipoprotein profile, insulin and glucose (HOMA-IR). Moreover, isolated TRL (d < 1006 g/l) were chemically characterized. In parallel, using randomly selected TRL from MetS patients with endothelial dysfunction (n = 6) and MetS patients with normal endothelial function (n = 6), the ability of TRL to inhibit ACh-induced vasorelaxation (10− 9–10− 5 mM) on aortic rings previously pre-contracted by noradrenaline (10− 8 mM) was evaluated. Results Interestingly, TRL isolated from MetS patients presenting endothelial dysfunction showed triglyceride over-enrichment (59.1 ± 4.8 vs. 54.1 ± 4.7%; p = 0.04), even after adjusting by potential confounders (p = 0.05). In addition, while TRL resulting from both MetS groups significantly inhibited endothelium dependent vasorelaxation (p < 0.001), TRL from MetS patients with endothelial dysfunction showed a strong tendency to a greater inhibition of vasorelaxation (p = 0.06). Moreover, TRL-triglyceride (%) showed a strong tendency to correlate with the grade of vasorelaxation inhibition exerted by TRL (r = 0.60; p = 0.05). Conclusion These results, taken together, would allow inferring for the first time that the predominance of triglyceride over-enriched TRL in circulation in MetS would induce endothelial dysfunction, contributing to the inherent cardiovascular risk of MetS.Fil: Lucero, Diego Martín. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: López, Graciela I.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaFil: Gorzalczany, Susana Beatriz. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Duarte, Mariano. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: González Ballerga, Esteban. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Sordá, Juan. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Schreier, Laura Ester. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaFil: Zago, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentin