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841 CIRCULATING LEVELS OF TNF-LIKE CYTOKINE 1A (TL1A) AND ITS DECOY RECEPTOR 3 (DCR3) IN NASH: MARKERS OF ADVANCED DISEASE
POSTERS This work is part of the project “Hepatic and adipose tissue and functions in the metabolic syndrome” (HEPADIP), which is supported by the European Commission as an Integrated Project under the 6th Framework Programme (Contract LSHM-CT-2005– 018734). 840 DECREASED POSTPRANDIAL FGF-19 SERUM LEVELS IN NON-OBESE NAFLD PATIENTS D. Friedrich, F. Lammert. Department of Internal Medicine II, Saarland University Hospital, Homburg, Germany E-mail: [email protected] Background: FGF-19, a novel intestinal hormone, is secreted in the terminal ileum postprandially and during bile salt absorption. Non-alcoholic fatty liver disease (NAFLD) is common in obesity but the molecular mechanisms of NAFLD development in non-obese patients remain yet to be defined. FGF-19 might play a protective role in NAFLD by improving insulin sensitivity, increasing hepatic beta-oxidation and inhibiting lipogenesis. The aim of our study was to investigate FGF-19 serum concentrations in non-obese (BMI <30 kg/m2 ) individuals with NAFLD in comparison to obese (BMI >30 kg/m2 ) patients and healthy volunteers in a fasted state and after a defined oral fat load. Patients and Methods: In total, 14 NAFLD patients (mean BMI 27.7 kg/m2 ), 21 obese individuals and 16 healthy controls were recruited. FGF-19 levels were determined by ELISA after 10 hours of overnight fasting. Subsequently, all individuals received 1 g fat (Calogen® ) per kg body weight orally. FGF-19 serum concentrations were measured at baseline and after 2, 4 and 6 hours. No other food intake was permitted during this time but water was allowed ad libitum. Results: Basal serum FGF-19 levels in the fasted state do not differ between overweight NAFLD patients, obese subjects and normal controls. The oral fat load increases FGF-19 levels in all three groups. FGF-19 serum levels peak after 4 hours in all three groups and were highest in controls (378.9±202.1 pg/ml). In comparison to men, women display significantly higher FGF-19 levels after 6 hours (283.4±189.6 vs. 172.1±82.1 pg/ml, p < 0.05). Of note, non-obese NAFLD patients display the lowest FGF-19 levels at all time points. In particular, FGF-19 levels 2 hours post oral fat load are significantly lower (p = 0.004) in overweight NAFLD patients (143.7±61.4 pg/ml) as compared to both healthy volunteers and obese patients (287.4±177.7 pg/ml and 281.4±235.0 pg/ml respectively). Conclusions: We established an oral fat load test (“OFLT”), which demonstrated impaired FGF-19 release in non-obese NAFLD patients. The hepatic mechanisms consequences of impaired FGF-19 signaling require further investigation. 841 CIRCULATING LEVELS OF TNF-LIKE CYTOKINE 1A (TL1A) AND ITS DECOY RECEPTOR 3 (DCR3) IN NASH: MARKERS OF ADVANCED DISEASE A.-K. Gantzarou1 , V. Kotoula2 , S. Kim3 , G. Germanidis4 , I. Goulis1 , G. Koustiani1 , M. Pape5 , K. Mandraveli5 , P. Hytiroglou2 , E. Akriviadis1 . 1 4th Unit of Internal Medicine, Hippokration General Hospital of Thessaloniki, 2 Department of Pathology, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3 BioPower Tech, Tuscaloosa, AL, USA; 4 1st Internal Medicine Unit, AHEPA University Hospital of Thessaloniki, Aristotle University of Thessaloniki, 5 Laboratory of Infectious Diseases, AHEPA University Hospital of Thessaloniki, Thessaloniki, Greece E-mail: [email protected] Background and Aims: TL1A is a ligand of the TNF superfamily, with known apoptotic, immunostimulant and angiostatic properties, whereas DcR3 is its inhibitory decoy receptor. The aim of this study was to explore the possible involvement of this system of molecules in NASH. S336
Methods: Sera and liver biopsies were collected from 22 NASH patients. ELISA was used to measure TL1A and DcR3 levels, as well as those of the hepatocellular apoptosis marker cytokeratin 18 fragments (CK18), in serum samples of patients and normal controls. Comparison to normal controls was performed by 2-tailed t-test. Correlations among the 3 molecules, as well as variations according to the histological grade and stage of disease, were analyzed with Pearson’s correlation, and ANOVA, followed by multiple Bonferroni comparisons, respectively. Results: There were no statistically significant elevations of DcR3 and TL1A levels in comparison to normal controls, in the entire NASH group (p = 0.177 and 0.172, respectively). However, patients with cirrhosis had significantly higher DcR3 levels compared to those with all other stages of disease [p < 0.01 for the differences between stage 4 (cirrhosis) and all other stages of disease]. Moreover, a tendency for higher DcR3 levels was observed in patients with moderate to severe inflammation, compared to those with mild inflammation (p = 0.1). There was also a tendency for variation of TL1A levels, according to stage of disease (ANOVA p = 0.087), with higher levels observed in stage 4 patients. Hepatocellular apoptosis marker CK18 was significantly elevated in NASH patients, compared to normal controls (p < 0.0001), showing no variation according to stage of disease (ANOVA p = 0.928). There was a strong positive correlation between DcR3 and TL1A levels (r = 0.979, p < 0.0001), but no correlation between either DcR3 or TL1A and CK18 levels. Conclusions: DcR3 and TL1A levels predict advanced disease stage in NASH and appear to be better markers in this context than apoptosis marker CK18. These results suggest that immunological markers could be of use in the noninvasive assessment of advanced NASH. 842 PREDISPOSITION TO DEVELOP DIABETES IN SUBJECTS WITH NAFLD IS RELATED TO INSULIN RESISTANCE RATHER THAN TO DECREASED B-CELL FUNCTION A. Gastaldelli1,2 , R. Petz1 , A. Ricotti1 , E. Cersosimo2 , K. Cusi2 , R. DeFronzo2 . 1 Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy; 2 Division of Diabetes, UTHSCSA, San Antonio, TX, USA E-mail: [email protected] Background and Aims: Epidemiological studies have shown that non-alcoholic fatty liver disease (NAFLD) is a risk factor for the development of type 2 diabetes (T2DM). As the subjects become insulin resistant (IR) their glucose tolerance is maintained until the beta-cell is able to secrete enough insulin to overcome the IR status. Beta-cell dysfunction is therefore a major defect that leads to hyperglycemia and T2DM. Subjects with NAFLD are often IR and have reduced hepatic insulin clearance. The aim of this study was to evaluate if beta-cell function is impaired in subjects with NAFLD and for this they are more prone to develop T2DM. Methods: We analyzed the glucose, insulin and FFA profile (at 0, 30, 60, 90 and 120 min) after 75 gr of glucose (OGTT) in 148 subjects (n = 34 NGT, n = 24 IGT and n = 90 T2DM) in which we also measured liver fat (LF) by magnetic resonance spectroscopy (MRS). We assessed peripheral insulin sensitivity (as OGIS index), adipose tissue insulin resistance index (Adip_IR = FFA×Insulin), while insulin secreted in response to OGTT, i.e., the beta-cell function, was evaluated as the ratio of incremental area under the curve of insulin to glucose (DAUC-I/DAUC-G). We also evaluated the disposition index (DI = OGIS×DAUC-I/DAUC-G). Decreased values of the DI were used as indicators of a predisposition to become T2DM. Results: LF was 7.5±1.4% (range 0–28%) in NGT, 19.8±2.5% (3–41%) in IGT, 18.5±1.2% (0–52%) in T2DM. LF was significantly correlated with AUC-glucose (r = 0.24), AUC-Insulin (r = 0.28), AUCFFA (r = 0.31) during OGTT, peripheral-IR (r = 0.49) and Adip-IR
Journal of Hepatology 2011 vol. 54 | S209–S361
Methods: Sera and liver biopsies were collected from 22 NASH patients. ELISA was used to measure TL1A and DcR3 levels, as well as those of the hepatocellular apoptosis marker cytokeratin 18 fragments (CK18), in serum samples of patients and normal controls. Comparison to normal controls was performed by 2-tailed t-test. Correlations among the 3 molecules, as well as variations according to the histological grade and stage of disease, were analyzed with Pearson’s correlation, and ANOVA, followed by multiple Bonferroni comparisons, respectively. Results: There were no statistically significant elevations of DcR3 and TL1A levels in comparison to normal controls, in the entire NASH group (p = 0.177 and 0.172, respectively). However, patients with cirrhosis had significantly higher DcR3 levels compared to those with all other stages of disease [p < 0.01 for the differences between stage 4 (cirrhosis) and all other stages of disease]. Moreover, a tendency for higher DcR3 levels was observed in patients with moderate to severe inflammation, compared to those with mild inflammation (p = 0.1). There was also a tendency for variation of TL1A levels, according to stage of disease (ANOVA p = 0.087), with higher levels observed in stage 4 patients. Hepatocellular apoptosis marker CK18 was significantly elevated in NASH patients, compared to normal controls (p < 0.0001), showing no variation according to stage of disease (ANOVA p = 0.928). There was a strong positive correlation between DcR3 and TL1A levels (r = 0.979, p < 0.0001), but no correlation between either DcR3 or TL1A and CK18 levels. Conclusions: DcR3 and TL1A levels predict advanced disease stage in NASH and appear to be better markers in this context than apoptosis marker CK18. These results suggest that immunological markers could be of use in the noninvasive assessment of advanced NASH. 842 PREDISPOSITION TO DEVELOP DIABETES IN SUBJECTS WITH NAFLD IS RELATED TO INSULIN RESISTANCE RATHER THAN TO DECREASED B-CELL FUNCTION A. Gastaldelli1,2 , R. Petz1 , A. Ricotti1 , E. Cersosimo2 , K. Cusi2 , R. DeFronzo2 . 1 Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy; 2 Division of Diabetes, UTHSCSA, San Antonio, TX, USA E-mail: [email protected] Background and Aims: Epidemiological studies have shown that non-alcoholic fatty liver disease (NAFLD) is a risk factor for the development of type 2 diabetes (T2DM). As the subjects become insulin resistant (IR) their glucose tolerance is maintained until the beta-cell is able to secrete enough insulin to overcome the IR status. Beta-cell dysfunction is therefore a major defect that leads to hyperglycemia and T2DM. Subjects with NAFLD are often IR and have reduced hepatic insulin clearance. The aim of this study was to evaluate if beta-cell function is impaired in subjects with NAFLD and for this they are more prone to develop T2DM. Methods: We analyzed the glucose, insulin and FFA profile (at 0, 30, 60, 90 and 120 min) after 75 gr of glucose (OGTT) in 148 subjects (n = 34 NGT, n = 24 IGT and n = 90 T2DM) in which we also measured liver fat (LF) by magnetic resonance spectroscopy (MRS). We assessed peripheral insulin sensitivity (as OGIS index), adipose tissue insulin resistance index (Adip_IR = FFA×Insulin), while insulin secreted in response to OGTT, i.e., the beta-cell function, was evaluated as the ratio of incremental area under the curve of insulin to glucose (DAUC-I/DAUC-G). We also evaluated the disposition index (DI = OGIS×DAUC-I/DAUC-G). Decreased values of the DI were used as indicators of a predisposition to become T2DM. Results: LF was 7.5±1.4% (range 0–28%) in NGT, 19.8±2.5% (3–41%) in IGT, 18.5±1.2% (0–52%) in T2DM. LF was significantly correlated with AUC-glucose (r = 0.24), AUC-Insulin (r = 0.28), AUCFFA (r = 0.31) during OGTT, peripheral-IR (r = 0.49) and Adip-IR
Journal of Hepatology 2011 vol. 54 | S209–S361