An Image/Link below is provided (as is) to download presentation
Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.
Obesity is a chronic inflammatory condition and obesity has been claimed one of risk factors for cardiovascular disease, stroke, diabetes mellitus and cancers. The metabolic syndrome includes hypertension, hyperlipidemia, diabetes mellitus and fatty liver disease. Nonalcoholic fatty liver disease (NAFLD) is considered a hepatic manifestation of systemic metabolic syndrome. NAFLD is a wide spectrum of liver damage, ranging from simple steatosis, to nonalcoholic steatohepatitis (NASH) and cirrhosis on the basis of longstanding fatty change of the liver. While NASH implies a risk of progressive liver disease, simple steatosis is regarded as a benign condition. The “two hit hypothesis” has become an important theoretical framework for understanding the pathogenesis of NAFLD. The “first hit” is liver fat accumulation in hepatocytes, linked with insulin resistance. In the majority of patients with excess liver fat or scarce hepatic inflammation, this condition will be termed simple steatosis. However, a “second hit” may trigger the necroinflammatory response characterizing NASH through abnormal cytokine production and oxidative stress. The mediated abnormal cytokine production including adiponectin, leptin and tumor necrosis factor -?恁]TNF-?恁^. TNF-?? is a proinflammatory cytokine, whereas leptin has fibrogenetic effect. In contrast, adiponectin play antidiabetic and anti-inflammatory role that acts as a fascinating mediator linking adipose tissue, insulin resistance, and inflammation. Adiponectin may have protective effect on the development of NAFLD, potentially antagonizing the effect of TNF-??. Although the participation of inflammatory mediators and cytokines in the pathogenesis of NAFLD is widely recognized, their relative important in Taiwanese obese patients is not fulfilled. In this study, we analyzed the clinicopathology of morbidly obese patients (BMI?d35) from liver biopsied specimens. To further elucidate the role of inflammation in NAFLD, we evaluated mRNA and protein expression of leptin, TNF-??, and anti-inflammatory factor adiponectin and adiponectin receptor II (adopoRII) in liver tissues of NAFLD patients.Our study enrolled 40 obese patients, including 12 men and 28 women with mean age 29.43 ± 9.19 years, and the mean BMI was 44.79 ± 5.37 kg/m2. Histologic evidence of NASH (NAS ≧5) was present in 30 patients (75%). Of these 30 patients, 11 patients were grouped as NASH with stage 0-1 mild liver fibrosis and 19 patients were grouped as NASH with stage 2-4 advanced liver fibrosis. The other 10 patients had normal liver histology or simple steatosis only without necroinflammation (NAS<3) and they were considered as control group. The serum levels of alanine transaminase (ALT) (p =0.000), aspartate transaminase (AST) (p =0.000), γ-glutamyl transferase (GGT) (p =0.045) and hemoglobin A1c (HbA1c) (p =0.001) have statistically difference in these three groups. Only AST was independently different after multivariate logistic regression analysis.Hepatic steatosis was present in 36 patients (90%). Ballooning degeneration of hepatocytes was occurred in all NASH group. Lobular inflammation found in 39 patients (97.5%). Of these 39 patients, 11 (27.5%), 13 (32.5%) and 15 (37.5%) presented with mild, moderate and severe lobular inflammation. Regarding the stage of fibrosis, only one patient presented without fibrosis. No obvious stage 4 fibrosis (or liver cirrhosis) was noted in any of the cases. The mRNA of leptin was undetectable in the liver tissue of any cases in our study. TNF-α/GAPDH cDNA ratio was highest in patients without NASH, while the adiponectin/GAPDH cDNA ratio tended to be higher in NASH with advanced liver fibrosis. In contrast, the adipoRII/GAPDH cDNA ratio was lower in NASH with advanced liver fibrosis. All the mRNA levels of the studied genes have not reached significantly different. Immunohistochemistry, adiponectin and adipoRII staining were less pronounced in liver sinusoids in NASH group compared with non-NASH group. In contrast, leptin staining was more pronounced in liver tissues of NASH group with advanced liver fibrosis. However, no significant difference between three groups was noted.The clinicopathological correlation demonstrated that the degree of hepatic steatosis was best correlated with fasting sugar, AST, ALT, GGT, triglyceride and HbA1c. Inverse relationship was noted between hepatic steatosis and high density lipoprotein. Independent predictors of ballooning degeneration were serum fasting sugar, AST, ALT and HbA1c. The best predictors of lobular inflammation were AST, ALT and HbA1c. The predictors for liver fibrosis were AST, ALT and C-peptide. In addition, the predictor for adiponectin/GAPDH cDNA ratio was inversely correlated to uric acid level; and the predictor for TNF-α/GAPDH cDNA ratio was related to liver steatosis. Immunohistochemistry study showed that the best predictors of leptin expression were correlated with C-peptide and portal inflammation. AdipoRII immunohistochemical stain was inversely related with systolic blood pressure; and positively associated Mallory body and glycogenated nuclei. Finally, the predictors for TNF-α immunohistochemical expression were AST, hemoglobin, lobular inflammation, portal inflammation and NAS activity. No significantly predictor of adiponectin immunohistochemical expression was noted.Insulin resistance and reduced whole-body insulin sensitivity are major characteristics of NAFLD. In our study, we could not completely address the complex association between TNF-α, leptin and adiponectin/adipoRII, insulin, liver steatosis, necroinflammation, and liver fibrosis. Therefore, the possibility that all these adipocytokines could influence necroinflammation and fibrosis, finally to the functional severity in NASH, is not completely understood. Larger studies are needed to fully establish the pathogenesis and mechanisms of fat accumulation in the liver and the progression to fibrosis. Finally, the relationship between hepatic and peripheral insulin resistance and the development of hepatic steatosis should be clarified in future research.