Comparative Profiling of Circulatory Levels of Adipokines and Cytokines in Patients With Various Types of Non Alcoholic Fatty Liver Disease




Jarrar, Mohammed

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Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the most common cause of liver disease. The NAFLD spectrum ranges from simple benign steatosis to NASH to fibrosis and cirrhosis. Omental adipose tissue is a biologically active organ that plays a role in pathogenesis of NAFLD. Expansion of adipose tissue mass accompanied by alteration in adipocytokines could be a prominent mechanism in the pathogenesis and progression of NAFLD. Adipocytokines play a role in insulin resistance, oxidative stress and hepatocyte apoptosis and may be there is imbalance in their serum levels in NAFLD spectrum and the degree of insulin resistance. Accordingly, we explored the differences in the level of transcription of genes in adipose tissue and liver as well as adipocytokines serum levels in different types of NAFLD. This would help to identify non-invasive diagnostic marker profiles for early distinction between NASH and steatosis. In this study of gene expression analyses, we show that there is a prominent adipose-specific deregulation of the inflammation and immune system related genes in NASH. In addition, there are increases in the hepatic detoxification enzymes in obese patients. A number of liver and adipose-specific functional networks centered by TNFalpha, JUN/JUNB and IFNgamma were highlighted in relation to the NASH pathogenesis. Our results also show that serum levels of TNF-α and IL-8 were significantly higher in NAFLD patients compared to both obese and non-obese controls. Univariate analyses involving all patients revealed a significant correlation between serum concentrations of TNF-α and IL-8, as well as between IL-6 and IL-8. Insulin resistance measured by homeostasis model assessment (HOMA) scores negatively correlated with serum Adiponectin levels in NAFLD patients. Serum Visfatin was significantly higher in steatosis and obese controls than the non-obese controls. Visfatin and IL-6 serum levels in NASH patients were lower in comparison to patients with steatosis implicating their possible co-regulated protective role from progression of steatosis to NASH. Multivariate analyses revealed that TNF-α serum level levels influenced mainly by serum glucose, HOMA, BMI and IL-8 in NAFLD, while IL-6 levels influenced mainly by HOMA scores and IL-8. A multivariate analysis indicated that TNF-α was the only independent predictor of histologic fibrosis in patients with NASH. Apoptosis per se, measured by levels of Ck-18 cleaved at Asp396-neoepitope and secreated to the circulation is significantly increased in the serum of NASH patients in comparison to patients with steatosis and BMI matched morbidly obese patients. In NAFLD and obese controls, both apoptosis and total cell death measured by serum levels of intact CK18, closely correlated with TNF-α levels and IL-8, but in NAFLD apoptosis and total cell death only correlated with TNF-α. Of special importance, NASH could be reliably predicted by a combination of apoptosis, necrosis, serum Adiponectin and serum Resistin, with sensitivity of 95.45%, specificity of 70.21%, and AUC of 0.908. HCV infection is clearly characterized by alterations in cytokine serum levels. There are significant differences in serum levels of major pro-inflammatory cytokines (IL-6, IL-8 and TNF-α) between patients groups with HCV infection regardless of genotype or association with steatosis when compared to group of patients with steatosis only. In addition, IL-8 and TNF-α were significantly increased in HCV3 infections compared to HCV1. Some of these cytokines play more prominent roles in development of steatosis accompanied by HCV infection. Our data shows that there is strong connection between the HCV genotype 3, steatosis and increases in IL-8 serum levels. Multiple correlation analyses showed that steatosis in HCV is mostly dependent on IL-6 and IL-8; in HCV1 on IL-6, TNF-α and IL-1B while in HCV3 is mostly dependent on IL-8. Actually HCV3 associated steatosis can be predicted by serum levels of IL-8 with 87.5% specificity, 100% sensitivity and AUC of 0.931.



NAFLD, Adipokines, Cytokines, NASH, MS, Hepatitis C