Non-alcoholic Fatty Liver Disease In Individuals Research Articles

Statin Use Is Not Associated With Presence of and Severity of Nonalcoholic Fatty Liver Disease

There is concern that statin use may exacerbate nonalcoholic fatty liver disease (NAFLD). We aimed to assess the association of statin use with NALFD and severity of liver fibrosis among NAFLD individuals. We evaluated 6,385 cross-sectional healthy Brazilian subjects (43 ± 10 years, 79% males) without clinical coronary heart disease between November 2008 and July 2010. NAFLD was diagnosed by ultrasound. Severity of liver fibrosis was predicted by fatty liver index and FIB-4. NAFLD prevalence was 36% (n = 2310). Overall 552 (9%) individuals were using statins of whom 49% had NAFLD. Statin users were more likely to be men, older age, and have higher burden of risk factors (p <0.05). In age gender adjusted analysis the odds ratio for NAFLD with statin use was 0.87 (0.61-1.25, p = 0.46) in the presence of metabolic syndrome and 1.08 (0.88-1.32, p = 0.56) in its absence. On further adjustment for metabolic risk factors, LDL and smoking the results remained unchanged (OR: 0.89, 95% CI: 0.65-1.32, p = 0.56 and 0.90 (0.69-1.18, p = 0.46). There was no significant association between statin use and fatty liver index in a subanalysis of NAFLD individuals (71 ± 18 vs. 69 ± 23, p = 0.18). Although FIB-4 was mildly elevated with statin use (1.20 ± 0.51 vs. 1.02 ± 0.46, p <0.001), a multivariate analysis adjusted for age, gender and risk factors revealed statin use was not associated with severe fibrosis (FIB >1.45) (OR 0.88, 95% CI: 0.60-1.29, p = 0.50). The results of this study favor statin use in subjects with NAFLD as its use is not associated with the presence of NAFLD or increased fibrosis.

Exercise training improves cutaneous microvascular function in nonalcoholic fatty liver disease

The leading causes of mortality in nonalcoholic fatty liver disease (NAFLD) relate to cardiovascular disease (CVD). The contribution of nitric oxide (NO) to endothelial function, a surrogate of CVD risk, is currently unknown in NAFLD. We hypothesize that NO-mediated cutaneous microvessel function would be impaired in NAFLD compared with controls and that exercise would enhance microvessel function compared with conventional care. Thirteen NAFLD patients (aged 50 ± 3 yr, BMI 31 ± 1 kg/m²) and seven controls (48 ± 4 yr, 30 ± 2 kg/m²) were studied. NAFLD patients were randomized to either 16 wk of exercise or conventional care. Cutaneous microvessel function was examined using laser Doppler flowmetry combined with intradermal microdialysis of N(G)-monomethyl-l-arginine to assay the NO dilator response to local forearm heating. Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively, and cardiorespiratory fitness was assessed. Differences in NO contribution to cutaneous blood flow between NAFLD and control individuals and between interventions were analyzed using general linear modeling. NO contribution to cutaneous blood flow was similar between NAFLD and controls (P = 0.47). Cardiorespiratory fitness was greater following exercise training compared with conventional care. NO contribution to cutaneous blood flow in response to heating at 42°C was 20.4% CVCmax (95% CI = 4.4, 36.4) greater following exercise training compared with conventional care (P = 0.02). Exercise training improves cutaneous microvascular NO function in NAFLD patients. The benefit of exercise training compared with conventional care strongly supports a role for exercise in the prevention of CVD in NAFLD.

Analysis of cytotoxic T-lymphocyte-associated antigen-4 and MMP-9 genes′ methylation and their expression profiles with risk of non-alcoholic fatty liver disease

OBJECTIVE:To investigate the effect of promoter methylation of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene and matrix metalloproteinases (MMPs) on the risk of non-alcoholic fatty liver disease (NAFLD).MATERIALS AND METHODS:CTLA-4 and MMP-9 promoter methylation were investigated using a methylation-specific polymerase chain reaction (MS-PCR) in blood samples taken from 80 NAFLD individuals and 95 healthy controls. The expression levels of CTLA-4 and MMP-9 were also assessed in 10 blood and 9 liver tissues mRNA samples from NAFLD patients. These cases were compared to the blood (n = 10) samples of healthy controls with real-time quantitative reverse transcriptase PCR.RESULTS:No significant relationship was found for methylation of CTLA-4 and MMP-9 between cases and controls. The relative expression of CTLA-4 and MMP-9 mRNA in NAFLD was not significantly different compared to healthy control samples.CONCLUSION:For the first time, our outcomes indicate that the methylation status of CTLA-4 and MMP-9 genes has no significant function on the process of NAFLD.

Liver repercussions of defective gut surveillance

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty per cent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet the causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models reveal that inflammasome-deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic tumour- necrosis factor (TNF)-α expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient mice with wild-type mice results in exacerbation of hepatic steatosis and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders.

Lipidic last breath of life in patients with alcoholic liver disease

Alcoholic liver disease (ALD) begins with the accumulation of lipid droplets in the liver. Lipids which accumulate in the liver can stimulate inflammation, and the fatty acid derivatives, hydroxyeicosatetraenoic acids (HETEs) and hydroxyoctadecadienoic acids (HODEs), may play an important role in this process.We evaluated the concentrations of linoleic and arachidonic acid derivatives in the plasma of patients with ALD, non-alcoholic fatty liver disease (NAFLD) and healthy individuals. The groups consisted of 173 subjects: 63 patients with ALD, 90 with NAFLD and 20 healthy volunteers. Plasma 12-, 15-, and 5-HETE as well as 9- and 13-HODE were assessed using HPLC and isoprostane 8-epi-PGF 2α III was evaluated with an ELISA. In addition the mRNA expression of lipoxygenases (5-LOX, 15-LOX-1, 15-LOX-2) in the liver samples of patients with ALD cirrhosis was measured. A significant difference between the plasma concentrations of the analyzed derivatives was found when divided according to gender. The most significant differences were found between healthy individuals and ALD patients, as well as ALD and NAFLD individuals regardless of gender. The increased plasma HODEs and HETEs concentrations were in line with the increase in 5- and 15-LOX-1 and 15-LOX-2 mRNA in liver samples from ALD cirrhosis patients. LOXs expression and peroxidation of polyunsaturated fatty acids by free radical-propagated chemical oxidation may be contributing factors in liver necroinflammatory injury in ALD.

The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

These recommendations are based on the following: (1) a formal review and analysis of the recently published world literature on the topic [Medline search up to June 2011]; (2) the American College of Physicians’ Manual for Assessing Health Practices and Designing Practice Guidelines; (3) guideline policies of the three societies approving this document; and (4) the experience of the authors and independent reviewers with regards to NAFLD. Intended for use by physicians and allied health professionals, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible and adjustable for individual patients. Specific recommendations are evidence-based wherever possible, and when such evidence is not available or inconsistent, recommendations are made based on the consensus opinion of the authors. To best characterize the evidence cited in support of the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1). The strength of recommendations in the GRADE system is classified as strong (1) or weak (2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (A), moderate (B) or low-quality (C). This is a practice guideline for clinicians rather than a review article and interested readers can refer to several comprehensive reviews published recently.

935 Light Alcohol Consumption is Associated With Lower Prevalence of NAFLD: the Multi Ethnic Study of Atherosclerosis (MESA)

Introduction: Non alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in the United States. It is commonly associated with metabolic comorbidities such as obesity, diabetes, and metabolic syndrome. Heavy alcohol consumption is unequivocally associated with hepatic steatosis, but recent epidemiological studies suggest that non-heavy alcohol consumption may be associated with lower prevalence of NAFLD. In a recent study of 7000 Japanese individuals by Moriya et al found the prevalence of hepatic steatosis was 50% lower in light to moderate drinkers compared to nondrinkers . Aim: To compare the prevalence of NAFLD in individuals with light alcohol consumption and total abstainers among the MESA participants. Methods: We studied the entire MultiEthnic Study of Atherosclerosis (MESA) cohort; a population-based cohort of 6,814 Caucasian, African American, Hispanic, and Asian adults free from clinical cardiovascular disease. Cardiac CT scans were performed on all the participants, and liver and spleen images were available in > 90% of the CT scans. NAFLD was defined as liver/spleen attenuation 14 drinks on average per week in men and > 7 drinks on average per week in women). Light alcohol consumption was defined as 114 drinks per week in men and 1-7 drinks per week in women. Univariate and multivariate analyses were conducted to examine the relationship between light alcohol consumption and NAFLD. Results: After exclusions, there were a total of 2033 participants; 876 abstainers and 1,157 light drinkers. The total prevalence of NAFLD was 17%. The prevalence of NAFLD among light drinkers was significantly lower than in abstainers (14.8% vs. 18.5% OR:0.77, 95% CI 0.600.97, p=0.026). Age, gender, race, and the prevalence of metabolic syndrome were significantly different between the two groups (Table 1). The relationship between light alcohol consumption and lower prevalence of NAFLD persisted after controlling for age, gender, and race in the multivariate analysis (OR: 0.78, 95% CI: 0.61-0.99, p=0.049). However, the significance of this relationship disappeared once the metabolic syndrome was added to the multivariate analysis (OR: 0.88, 95%CI: 0.68-1.14, p=0.35). Similarly, the significant relationship between light drinking and lower prevalence of NAFLD disappeared by simply controlling for the presence of metabolic syndrome (OR:0.89, 95%CI: 0.69-1.14, p=0.36). Conclusion: Compared to abstainers, light drinkers have a lower prevalence of NAFLD. However, this relationship appears dependent on the metabolic syndrome, suggesting that light alcohol consumption's protective effect against NAFLD is possibly mediated through its effect on the metabolic syndrome. Table 1: Selected clinical characteristics of abstainers and light drinkers

Serum paraoxonase and arylesterase activities in Iranian patients with nonalcoholic fatty liver disease

BackgroundThe aim of the study was to investigate paraoxonase-1 (PON1) and aryl esterase (ARE) activities in patients with nonalcoholic fatty liver disease (NAFLD). Materials and methodsThis case–control study was done on 83 subjects with confirmed NAFLD (50 male, 33 female, age; 40.46±12.13 years) and 138 healthy individuals (75 male, 63 female; age; 40.94±14.50 years). PON1, salt-stimulated PON1 and ARE activities were determined using paraoxon and phenyl acetate as substrate, respectively. ResultsThe levels of PON1 activities in NAFLD and healthy individuals were 90.83±63.65 IU/L and 79.41±68.14 IU/L, respectively. There was no significant differences regarding PON1 activity between NAFLD and healthy subjects (p=0.229). While, ARE activity was significantly higher in NAFLD (83.34±28.36 KU/L) than in normal subjects (64.06±27.49 KU/L) (p<0.001). ConclusionsOur results showed that PON1 activity is not a promising biomarker for the evaluation of NAFLD while arylesterase may have, but further studies in larger samples with different ethnic groups are required to validate our findings.

Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty percent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different animal models reveal that inflammasome deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic TNF-α expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient animals to wild type mice results in exacerbation of hepatic steatosis, glucose intolerance, and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders.

Common genetic variations inCLOCKtranscription factor are associated with nonalcoholic fatty liver disease

To investigate the role of gene variants and derived haplotypes of the CLOCK transcription factor in nonalcoholic fatty liver disease (NAFLD) and their relation with the disease severity. A total of 136 patients with NAFLD and 64 healthy individuals were studied. Liver biopsy was performed in 91 patients. Six tag SNPs showing a minor allele frequency > 10% (rs1554483 C/G; rs11932595 A/G; rs4580704 C/G; rs6843722 A/C; rs6850524 C/G and rs4864548 A/G) encompassing 117 kb of chromosome 4 and representing 115 polymorphic sites (r(2) > 0.8) were genotyped. rs11932595 and rs6843722 showed significant associations with NAFLD (empiric P = 0.0449 and 0.023, respectively). A significant association was also observed between clinical or histologic spectrum of NAFLD and rs1554483 (empiric P = 0.0399), rs6843722 (empiric P = 0.0229) and rs6850524 (empiric P = 0.00899) and between fibrosis score and rs1554483 (empiric P = 0.02697), rs6843722 (empiric P = 0.01898) and rs4864548 (empiric P = 0.02697). Test of haplotypic association showed that CLOCK gene variant haplotypes frequencies in NAFLD individuals significantly differed from those in controls (empiric P = 0.0097). Our study suggests a potential role of the CLOCK polymorphisms and their haplotypes in susceptibility to NAFLD and disease severity.