Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2

BACKGROUND/AIMS: To elucidate the role of systemic inflammation in nonalcoholic fatty liver disease (NAFLD). METHODS: Serum samples in 47 patients with histologically verified NAFLD (22 with simple steatosis and 25 with nonalcoholic steatohepatitis [NASH]), and in 30 age-, sex- and ethnicity-matched healthy controls, were assessed for (i) general markers of inflammation (C-reactive protein [CRP], tumor necrosis factor [TNF]-alpha, and interleukin [IL]-6), (ii) chemokines (CC-chemokine ligand [CCL] 2/monocyte chemoattractant protein [MCP]-1, CCL19 and CCL21), (iii) adipocytokines related to insulin resistance and inflammation (adiponectin and leptin) and (iv) a marker of oxidative stress (8-isoprostane-F2alpha). RESULTS: Serum levels of several inflammatory cytokines were increased in NAFLD as compared to controls, and IL-6 (P=0.017), CCL2/MCP-1 (P=0.008) and CCL19 (P=0.001), but not CRP (P=0.199), remained elevated also after correction for sex, body mass index (BMI) and age. Comparing NASH with simple steatosis, levels of TNF-alpha (P=0.024) and CCL2/MCP-1 (P=0.012) were elevated and adiponectin (in women) (P=0.001) were decreased also after adjustment for sex, BMI and presence of the metabolic syndrome. CONCLUSIONS: Our results indicate that patients with NAFLD are characterized by a low-grade systemic inflammation. The high CCL2/MCP-1 levels in NASH might be of importance for the conversion from simple steatosis to NASH.     

Metformin in patients with non-alcoholic fatty liver disease: A randomized,controlled trial

Objective. The antidiabetic agent metformin is regularly discussed as a promising treatment for non-alcoholic fatty liver disease (NAFLD), which is characterized by insulin resistance. However, the evidence for its beneficial effects is limited, and conflicting reports have been published. The purpose of this study was to conduct a randomized, double-blind, placebo-controlled trial to test whether metformin improves liver histology in patients with non-alcoholic fatty liver disease. Material and methods. Forty-eight patients with biopsy-proven NAFLD were randomized to treatment with metformin (n=24) or placebo (n=24) for 6 months. A second liver biopsy was obtained in all subjects who completed the trial (n=44). Data analyses are restricted to this group (per-protocol analyses). The primary outcome was changes in histologically assessed liver steatosis. Secondary outcomes were changes in NAFLD activity (NAS)-score, liver steatosis assessed by computed tomography (CT), liver transaminases, body-weight, metabolic variables and inflammatory markers. Results. No significant differences between treatment with metformin or placebo were observed for changes in liver steatosis, assessed either histologically or by CT, NAS-score, liver transaminases or on markers of insulin resistance or inflammation. In contrast, beneficial effects of metformin were observed on changes in body-weight (p<0.001), serum levels of cholesterol (p=0.004), LDL-cholesterol (p<0.001), glucose (p=0.032) and on HbA1c (p=0.020). Conclusions. Treatment with metformin for 6 months was no better than placebo in terms of improvement in liver histology in patients with NAFLD. Nevertheless, the use of metformin could still be beneficial in this group as it is associated with a reduction in serum levels of lipids and glucose. (ClinicalTrials.gov number, NCT00303537)     

Abnormal glucose tolerance is a predictor of steatohepatitis and fibrosis in patients with non-alcoholic fatty liver disease

Objective. The majority of patients with non-alcoholic fatty liver disease (NAFLD) have simple steatosis. A minority, however, present with non-alcoholic steatohepatitis (NASH), a condition that can lead to advanced fibrosis and cirrhosis. The frequencies of NASH and fibrosis among patients with NAFLD and sustained elevation of liver function tests (LFT) are uncertain. Our aim was to estimate these frequencies. We characterize a population with NAFLD, with special emphasis on insulin resistance and the metabolic syndrome, and study possible predictors for different stages of the disease. Material and methods. All referred patients with sustained elevation of LFT, radiological evidence or clinical suspicion of fatty liver, and absence of other liver disease, were invited to participate in our study in the period June 2002 to December 2004. Results. Of 129 patients who met the inclusion criteria, 88 underwent liver biopsy. NAFLD was verified in 83 of them. Among these patients, 59 (71%) had the metabolic syndrome, 41 (49%) had NASH and 36 (43%) had fibrosis. Abnormal glucose tolerance (T2DM or impaired glucose tolerance) was the only independent risk factor for NASH (OR: 3.14; 95% CI: 1.20–8.23). Independent predictors for fibrosis were abnormal glucose tolerance (OR: 3.83; 95% CI: 1.29–11.40) and body mass index (OR: 1.20; 95% CI: 1.06–1.36) per kg/m². Conclusions. Both NASH and fibrosis are frequently present among patients with NAFLD and sustained elevation of LFT. The probability of these potentially progressive stages of NAFLD increases with the presence of abnormal glucose tolerance.     

Abnormal glucose tolerance is a predictor of steatohepatitis and fibrosis in patients with non-alcoholic fatty liver disease

OBJECTIVE: The majority of patients with non-alcoholic fatty liver disease (NAFLD) have simple steatosis. A minority, however, present with non-alcoholic steatohepatitis (NASH), a condition that can lead to advanced fibrosis and cirrhosis. The frequencies of NASH and fibrosis among patients with NAFLD and sustained elevation of liver function tests (LFT) are uncertain. Our aim was to estimate these frequencies. We characterize a population with NAFLD, with special emphasis on insulin resistance and the metabolic syndrome, and study possible predictors for different stages of the disease. MATERIAL AND METHODS: All referred patients with sustained elevation of LFT, radiological evidence or clinical suspicion of fatty liver, and absence of other liver disease, were invited to participate in our study in the period June 2002 to December 2004. RESULTS: Of 129 patients who met the inclusion criteria, 88 underwent liver biopsy. NAFLD was verified in 83 of them. Among these patients, 59 (71%) had the metabolic syndrome, 41 (49%) had NASH and 36 (43%) had fibrosis. Abnormal glucose tolerance (T2DM or impaired glucose tolerance) was the only independent risk factor for NASH (OR: 3.14; 95% CI: 1.20-8.23). Independent predictors for fibrosis were abnormal glucose tolerance (OR: 3.83; 95% CI: 1.29-11.40) and body mass index (OR: 1.20; 95% CI: 1.06-1.36) per kg/m2. CONCLUSIONS: Both NASH and fibrosis are frequently present among patients with NAFLD and sustained elevation of LFT. The probability of these potentially progressive stages of NAFLD increases with the presence of abnormal glucose tolerance.     

A simple and efficient synthesis of [2H10]deuterated bromfenvinphos by the Perkow reaction

(E,Z)‐2‐bromo‐1‐(2,4‐dichlorophenyl)vinyl bis[ethyl‐²H₅] phosphate ([²H₁₀]bromfenvinphos), a regiospecifically deuterium‐labelled pesticide, was synthesized in two steps starting from [²H₆]ethanol, phosphorus trichloride and 2,4‐dichlorophenacylidene bromide, and fully characterized. The deuterated biologically active bromfenvinphos is an important compound for the advancement of environmental degradation testing and some mass spectrometric studies. Copyright © 2011 John Wiley & Sons, Ltd.     

A rapid chemokine response of macrophage inflammatory protein (MIP)-1α, MIP-1β and the regulated on activation,normal T expressed and secreted chemokine is associated with a sustained virological response in the treatment of chronic hepatitis C

The role of chemokines in chronic hepatitis C virus (HCV) infection is not fully understood. The present study aimed to characterize the baseline serum concentrations and the initial β-chemokine response to treatment with interferon-α and ribavirin with respect to the final clinical outcome of virological response to treatment. Serum concentrations of alanine aminotransferase (ALT) and of the CC subfamily chemokines [macrophage inflammatory protein (MIP)-1α, MIP-1β, monocyte chemoattractant protein (MCP)-1 and the regulated on activation, normal T expressed and secreted (RANTES) chemokine] were measured in patients with chronic HCV infection and in healthy individuals. Necroinflammation and fibrosis were scored in liver biopsies. Treatment outcomes were classified as with or without a sustained virological response after a full-course treatment according to the genotypes. The main treatment group consisted of 72 patients with chronic hepatitis C, whereas 24-h blood samples were available for 42 patients. Increased baseline levels of all CC chemokines were found in the two responder groups compared to the healthy controls, although significant levels were reached only for MIP-1α and MCP-1. No correlation was observed between chemokine levels and serum ALT levels, any histological necroinflammatory parameters, or the fibrosis grade. After 24 h of treatment, increases in MIP-1α, MIP-1β and RANTES levels were exclusively observed in the group with sustained virological response. MCP-1 was also significantly increased after 24 h in both responder groups, although no differences were observed between the two responder groups. In conclusion, an early MIP-1α, MIP-1β, and RANTES response may predict a sustained response to virological treatment.