A Decreased Response to Resistin in Mononuclear Leukocytes Contributes to Oxidative Stress in Nonalcoholic Fatty Liver Disease.

BACKGROUND: Deregulation of immune response and oxidative stress contribute to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Resistin is a physiological modulator of inflammation and redox homeostasis of different cell types. Increased resistin serum concentration and the direct association between resistin hepatic expression and NAFLD severity suggest that resistin participates in NAFLD pathogenesis. AIMS: To evaluate resistin-induced regulation of redox homeostasis in mononuclear leukocytes from NAFLD patients and controls. METHODS: We evaluated basal and resistin-mediated modulation of reactive oxygen species (ROS) and glutathione content by flow cytometry, and antioxidant enzyme activities by spectrophotometry. RESULTS: Peripheral blood mononuclear cells (PBMC) from NAFLD patients showed higher ROS content and glutathione peroxidase activity and lower glutathione content, superoxide dismutase and glutathione reductase activities than control PBMC. Resistin decreased ROS levels and superoxide dismutase activity and increased glutathione reductase and catalase activities in PBMC from controls but not from patients. Resistin decreased glutathione content in PBMC from control and NAFLD patients, with greater effect on patient cells. Basal and resistin-modulated ROS levels were directly associated with obesity-related risk factors for NAFLD. Hepatic myeloid cells and T-lymphocytes from NAFLD patients showed higher basal ROS content than cells from controls. Resistin decreased ROS levels in hepatic T-lymphocytes from controls but not from patients. CONCLUSIONS: Resistin regulates redox homeostasis in mononuclear leukocytes. A decreased response to resistin in leukocytes from NAFLD patients is associated with an impaired redox homeostasis.

Limited expression of TLR9 on T cells and its functional consequences in patients with nonalcoholic fatty liver disease.

BACKGROUND/AIMS: Toll-like receptors (TLRs) modulate T cell responses in diverse diseases. Co-stimulation of T cell activation via TLR9 induces production of interferon gamma (IFN-γ), priming of which is critical for differentiation of pro-inflammatory macrophages. These macrophages have a crucial role in nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the expression of TLR9 protein on T cells and the consequences of TLR9-mediated triggering of these cells in patients with NAFLD. METHODS: Our study included 34 patients with simple steatosis, 34 patients with nonalcoholic steatohepatitis, eight patients with NAFLD who met general diagnostic criteria but lacked histological diagnosis, and 51 control subjects. We used a synthetic TLR9 ligand to co-stimulate T cells. We measured TLR9 expression in liver and peripheral T cells and CD69 and IFN-γ as phenotypic markers of T cell activation and differentiation by flow cytometry. RESULTS: TLR9 expression on liver and peripheral T cells was lowest in patients with simple steatosis and was positively associated with anthropometric, biochemical, and histopathological features of NAFLD. In vitro co-stimulation of T cells from patients with simple steatosis induced a limited number of IFN-γ-producing CD8+ T cells. At baseline, these patients showed a low frequency of circulating type 1 CD8+ cells. CONCLUSION: The positive associations between TLR9 and anthropometric, clinical, and histological features and the crucial role of IFN-γ-in NAFLD suggest that limited TLR9 expression and production of IFN-γ play a protective role in patients with simple steatosis.

"Hepatic toxicity by methotrexate with weekly single doses associated with folic acid in rheumatoid and psoriatic arthritis. What is its real frequency?"

INTRODUCTION AND OBJECTIVES: Liver injury caused by methotrexate (MTX) has mostly been investigated without applying criteria for the assessment of causality of drug induced liver injury (DILI). Hence, the existence of DILI by MTX in many cases is debatable. This study aimed to describe the frequency and characteristics of liver injury caused by MTX, applying DILI diagnostic criteria. MATERIAL AND METHODS: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients who were treated with MTX in association with folic acid were included. Serial determinations of alanine amino transferase (ALT) and aspartate amino transferase (AST) were performed. The Roussel Uclaf Causality Assessment Method (RUCAM) was applied in cases of increases of ALT/AST over 1.5 upper limit of normal. Liver biopsy was considered when the total cumulative dosage (TCD) of MTX was ≥3.5g. RESULTS: A total of 43 patients were analyzed (median follow up 32 (range: 1-48) months; 3.33 ALT/AST determinations per year). Five subjects presented an increase of ALT/AST. All presented a RUCAM score for MTX≤2 (improbable). Three had a RUCAM score for non-steroidal anti-inflammatory drugs ≥7 (probable) and two patients presented non-alcoholic fatty liver disease. Five patients with no other cause for liver disease consented to liver biopsy (TCD MTX: median 5.1; range: 3.5-7.4g). No significant fibrosis or steatosis was evident on histology. CONCLUSIONS: No biochemical or significant histological liver toxicity for MTX was demonstrated when applying causality criteria for DILI. More studies with this methodology are necessary in order to improve the assessment of its frequency.

Ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin is safe and effective in HCV-infected patients in a real-life cohort from Latin America.

Information about the use of ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin (OBV/PTV/r/DSV ± RBV) in real-clinical practice in Latin America is scarce. We aimed to confirm safety and effectiveness of OBV/PTV/r/DSV ± RBV therapy in real-world setting. We analyzed a cohort of patients with genotype 1 infection treated with OBV/PTV/r/DSV ± RBV. Data on demographics, clinical features, safety, and virological response were retrospectively collected from 21 centers in Latin America. A total of 96 patients received OBV/PTV/r/DSV, associated with RBV in 68% of the cases. Most were genotype 1b (80%), 56 (58%) had cirrhosis, and 45 (47%) failed prior HCV treatment. Adverse events occurred in 62% of patients. The most common adverse events were pruritus (21%), hyperbilirubinemia (17%), and asthenia (17%). Five patients discontinued therapy prematurely due to hepatic decompensation, three of them were Child-Pugh B at baseline and one patient died due to multi-organ failure. Follow up HCV-RNA 12 weeks after completion of therapy was evaluated in all the patients and sustained virologic response rate was 97%. No virologic breakthrough was detected. Our study confirms that OBV/PTV/r/DSV treatment is highly effective in patients with chronic HCV without cirrhosis or with Child-Pugh A cirrhosis in non-European populations. Adverse events were often mild and rarely led to treatment discontinuation except for patients with Child-Pugh B cirrhosis or with previous history of hepatic decompensation. These results can support the development of public strategies to expand the access of OBV/PTV/r + DSV and other DAAs combinations in order to reduce the burden of HCV infection in our region.

[Liver diseases in rheumatoid and psoriatic arthritis]. / Enfermedades hepáticas en artritis reumatoidea y psoriásica.

OBJECTIVE: The aim of this study was to evaluate the prevalence, risk factors and features of liver diseases (LD) in rheumatoid and psoriatic arthritis. PATIENTS AND METHODS: From July 2007 to January 2010, 118 non-selected patients were consecutively examined. The assessment consisted of a medical record, biochemical studies and abdominal ultrasounds. The diagnosis of fatty liver disease was based on the ultrasound drug induced liver injury (DILI) was evaluated by the Maria-Victorino system criteria. Liver biopsy associated with chronic administration of methotrexate was performed using the histological classification of Kleiner et al. For the statistical analysis chi square test with Yates correction, Student's t test or Mann-Whitney test were applied when appropriate. In the multivariate analysis a binary logistic regression was used. The threshold of significance was P < 0.05. RESULTS: LD was diagnosed in 47 patients (39.8%). The most frequent LD was fatty liver disease in 35 patients (29.7%), followed by DILI in 15 (12.7%), associated with non-steroidal anti-inflammatory drugs (NSAID). In the multivariate analysis, obesity was the only independent risk factor associated with fatty liver disease [Odds ratio (OR) 6.4 (confidence interval (CI) 95%: 2.5-16.1; P = 0.000)] and fatty liver disease was the only risk factor associated with DILI [OR 7.7 (CI 95%: 2.0-30.0; P = 0.003)]. CONCLUSIONS: In our series, there was a high prevalence of LD, being fatty liver disease associated with obesity the most frequent finding. The second frequent disease was DILI, being fatty liver disease its main risk factor. The presence of obesity and the use of NSAIDs, especially in patients with steatosis, arise from our results as two conditions that require special care in handling this particular population.