R.J. Andrade

Obesity dependent metabolic signatures associated with nonalcoholic fatty liver disease progression

Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n=90) or diagnosed with NAFLD (steatosis, n=246; NASH, n=131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individuals level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values=0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention.

Hepatitis C virus infection alters lipid metabolism depending on IL28B polymorphism and viral genotype and modulates gene expression in vivo and in vitro.

Hepatitis C virus (HCV) interacts with lipid receptors to enter the cell, circulates as lipoviroparticle and is secreted as VLDL. We aimed to investigate the role of the rs12979860 polymorphism in the IL28B gene in 143 with chronic hepatitis C genotype 1, 144 infected with genotype 3, 90 genotype 4 and 413 noninfected individuals on lipid profile and to test the impact of HCV infection in an in vitro model on VLDL biosynthesis‐related gene expression rs12979860 polymorphism was analysed using real‐time PCR coupled to Fluorescence Resonance Energy Transfer (FRET). Huh7.5 (rs12979860 CT) and Huh7 (genotype CC) cells were infected with JFH‐1 particles and serum from patients infected with genotypes 1 and 3. Gene expression of apolipoprotein B (apoB), microsomal triglyceride transfer protein (MTP), acetyl CoA carboxylase (ACC), diacylglycerol acyltransferase 2 (DGAT2), diacylglycerol acyltransferase 1 (DGAT1) and low‐density lipoprotein receptor (LDLr) genes were determined by semiquantitative RT‐PCR in vivo and in vitro. Genotype CC rs12979860 polymorphism was associated with significantly higher serum LDL and total cholesterol levels in patients with hepatitis C genotype 1 but not in patients with hepatitis C genotype 3, genotype 4 and control (noninfected) population. Genotype CC was more often seen in genotype 3 and healthy people in comparison with genotype 1; P = 0.001. In vitro results showed that HCV infection promotes lipid metabolism gene expression induction depending on viral genotype, but to a lesser extent in cells with CT genotype. These results demonstrate that IL28B genotype influences lipid metabolism in patients with hepatitis C but not in noninfected and it seems to be viral genotype‐mediated. HCV infection modifies lipid‐related genes expression (DGAT1 and DGAT2) in cultured cells based on viral genotype and IL28 polymorphism.

Hepatic steatosis and severity-related factors in obese children.

Obesity is an important health‐care problem in developed countries. It is considered a multisystemic disease, but it may also affect the liver, thus provoking non‐alcoholic fatty liver disease. This disease has been less extensively studied among children than among adults. We propose to analyze the prevalence of hepatic steatosis among a pediatric population within an area in southern Europe besides the variables associated with its development and severity.

Hepatotoxicidad secundaria a fármacos de uso común

Resumen La importancia de las reacciones adversas hepaticas estriba principalmente en su potencial gravedad, no en vano son la causa mas frecuente de retirada de medicamentos del mercado farmaceutico. Las reacciones hepatotoxicas son casi siempre impredecibles (idiosincrasicas), es decir, que ocurren muy raras veces en individuos que toman dosis terapeuticas del compuesto, y no son detectadas casi nunca durante la fase de desarrollo. Aunque el cuadro clinico que se observa mas frecuentemente sea la hepatitis aguda icterica, las lesiones producidas por farmacos pueden simular cualquier enfermedad hepatica conocida. A pesar de que cualquier sustancia ajena al organismo puede ser causa de enfermedad hepatica, hay farmacos con mayor potencial hepatotoxico. Los grupos farmacologicos incriminados mas a menudo en casos de hepatotoxicidad son los antiinflamatorios no esteroideos, entre los cuales el mas comun es el diclofenaco, los antibioticos encabezados por la amoxicilina-acido clavulanico y los antituberculosos. El diagnostico se basa en la sospecha clinica inicial y se sustenta en una anamnesis exhaustiva con una secuencia temporal adecuada y la exclusion de causas alternativas de enfermedad hepatica. Por ultimo, dado que no hay una terapia especifica, salvo excepciones como la N-acetilcisteina, en la intoxicacion por paracetamol el tratamiento fundamental es la deteccion precoz del cuadro con la consiguiente retirada del agente causal. En este articulo se realiza una revision y descripcion de las caracteristicas de las reacciones de hepatotoxicidad producidas por los farmacos mas ampliamente prescritos en la poblacion general, incluyendo analgesicos, antimicrobianos, antidiabeticos, farmacos para el sistema cardiovascular y psicofarmacos.

Real-World Effectiveness and Safety of Oral Combination Antiviral Therapy for Hepatitis C Virus Genotype 4 Infection

&NA; Patients with hepatitis C virus (HCV) genotype 4 infection are poorly represented in clinical trials of second‐generation direct‐acting antiviral agents (DAAs). More data are needed to help guide treatment decisions. We investigated the effectiveness and safety of DAAs in patients with genotype 4 infection in routine practice. In this cohort study, HCV genotype 4‐infected patients treated with ombitasvir/paritaprevir/ritonavir (OMV/PTVr) + ribavirin (RBV) (n=122) or ledipasvir/sofosbuvir (LDV/SOF) ± RBV (n=130) included in a national database were identified and prospectively followed up. Demographic, clinical and virologic data and serious adverse events (SAEs) were analyzed. Differences between treatment groups mean that data cannot be compared directly. Overall sustained virologic response at Week 12 post treatment (SVR12) was 96.2% with OMV/PTVr+RBV and 95.4% with LDV/SOF±RBV. In cirrhotic patients, SVR12 was 91.2% with OMV/PTVr+RBV and 93.2% with LDV/SOF±RBV. There was no significant difference in SVR12 according to degree of fibrosis in either treatment group (P = .243 and P = .244, respectively). On multivariate analysis, baseline albumin <3.5 g/dL (OMV/PTVr) and bilirubin >2 mg/dL (both cohorts) were significantly associated with failure to achieve SVR (P < .05). Rates of SAEs and SAE‐associated discontinuation were 5.7% and 2.5%, respectively, in the OMV/PTVr subcohort and 4.6% and 0.8%, respectively, in the LDV/SOF subcohort. DAA‐based regimens returned high rates of SVR12, comparable to limited data from clinical trials, in cirrhotic and non‐cirrhotic HCV genotype 4 patients managed in a realworld setting. Safety profiles of both regimens were good and comparable to those reported for other HCV genotypes.

Imaging biomarkers for steatohepatitis and fibrosis detection in non-alcoholic fatty liver disease.

There is a need, in NAFLD management, to develop non-invasive methods to detect steatohepatitis (NASH) and to predict advanced fibrosis stages. We evaluated a tool based on optical analysis of liver magnetic resonance images (MRI) as biomarkers for NASH and fibrosis detection by investigating patients with biopsy-proven NAFLD who underwent magnetic resonance (MR) protocols using 1.5T General Electric (GE) or Philips devices. Two imaging biomarkers (NASHMRI and FibroMRI) were developed, standardised and validated using area under the receiver operating characteristic curve (AUROC) analysis. The results indicated NASHMRI diagnostic accuracy for steatohepatitis detection was 0.83 (95% CI: 0.73–0.93) and FibroMRI diagnostic accuracy for significant fibrosis determination was 0.85 (95% CI: 0.77–0.94). These findings were independent of the MR system used. We conclude that optical analysis of MRI has high potential to define non-invasive imaging biomarkers for the detection of steatohepatitis (NASHMRI) and the prediction of significant fibrosis (FibroMRI) in NAFLD patients.

Oxidized low-density lipoprotein antibodies/high-density lipoprotein cholesterol ratio is linked to advanced non-alcoholic fatty liver disease lean patients.

A small but significant proportion of patients with normal body mass index show non‐alcoholic fatty liver disease (NAFLD). Oxidized low‐density lipoprotein (LDL) is a powerful immunogenic molecule, which causes oxidative stress and produces antibodies (oxLDL‐ab). We aimed to analyze the role of oxLDL‐ab on histological features in lean‐NAFLD patients.

Oxidized LDL antibodies / HDL‐c ratio is linked to advanced disease in NAFLD lean patients

A small but significant proportion of patients with normal body mass index show non‐alcoholic fatty liver disease (NAFLD). Oxidized low‐density lipoprotein (LDL) is a powerful immunogenic molecule, which causes oxidative stress and produces antibodies (oxLDL‐ab). We aimed to analyze the role of oxLDL‐ab on histological features in lean‐NAFLD patients.

Fine-mapping butyrophilin family genes revealed several polymorphisms influencing viral genotype selection in hepatitis C infection

Host–viral genetic interaction has a key role in hepatitis C infection (HCV) and maybe in the viral selection. In a preliminary GWAS analysis, we identified BTN3A2 rs9104 to be associated with HCV genotype 1. Therefore, our aim was to determine the influence of BTN family on the selection of HCV genotype. We performed a fine-mapping analysis of BTN gene region in a cohort of chronic HCV infection (N=841), validating significant results in another independent chronic HCV infection cohort (N=637), according to selection of viral genotype. BTN3A2 rs9104, BTN3A2 rs733528, BTN2A1 rs6929846, BTN2A1 rs7763910 and BTN3A3 rs13220495 were associated with viral genotype selection. Interestingly, BTN3A2 rs9104 GG genotype was closely related to genotype 1 infection (80.7% (394/488) compared with genotype 3 infection (53.5% (23/43); P=0.0001) in patients harboring IL28B-CT/TT genotype, although this effect was not observed in IL28B-CC genotype. Similarly, BTN3A3 rs13220495 CC genotype was linked to genotype 3 infection (100% (32/32)) compared to genotype 1 (87.3% (137/157); P=0.028) in patients harboring IL28B-CC genotype, but did not in IL28B-CT/TT genotype. Genetic variants in the butyrophilin family genes may alter susceptibility to infection, selecting HCV genotype and influencing disease progression. BTN3A2 rs9104 was strongly associated with genotype 1 infection and the haplotype BTN3A3 rs13220495 CC+IL28B genotype CC was universal in patients with hepatitis C genotype 3a.

Toxicidad hepática por fármacos. Dónde estamos y hacia dónde caminamos

La infancia abarca un periodo caracterizado por el crecimiento y el desarrollo con un paulatino proceso de maduracion de organos y sistemas y la consiguiente variabilidad en la cinetica y en la respuesta a los farmacos, que convierten al nino en un sujeto especialmente vulnerable a los efectos adversos de los medicamentos. Sorprendentemente, apenas se han disenado estudios para investigar la eficacia y seguridad de los medicamentos en esta poblacion, por lo que las prescripciones se realizan sobre la base de considerar al nino “un adulto en miniatura”. Una revision detallada de estos controvertidos aspectos se sigue de la propuesta de establecer una red multicentrica y multidisciplinaria de vigilancia enfocada en el diagnostico de las hepatopatias asociadas a medicamentos en pediatria, donde se incorpore una actitud epidemiologica a las condiciones habituales de la practica clinica. Se propone un protocolo consensuado de recogida de datos de incidencias de hepatotoxicidad con criterios uniformes e internacionalmente aceptados de establecimiento de causalidad y de clasificacion de la lesion hepatotoxica.