weight loss in 12 months despite evidence of moderate to advanced fibrosis in a number of patients. The use of liver biopsy to "encourage" patients with NAFLD/NASH to lose weight does not appear to be an effective strategy in promoting subsequent weight loss.
similar patients who were not taking statins (Mean ± SE: 0.90±0.14 vs. 0.47±0.12, p< 0.05). Also, anti-endothelial cells IgM levels were significantly higher in patients with CAD without NAFLD who were taking statins as compared to the similar patients who were not taking statins (Mean ± SE: 555259±122036 channel shifts vs. 249619±79846 channel shifts, p< 0.05). In univariate analysis, statins use was significantly associated with presence of the expected factors such as hyperlipidemia, type 2 diabetes and CAD (OR: 2.97-7.93, p= 0.01 to <0.01). In the multivariate analysis, only hyperlipidemia [OR: 5.64 (95% CI: 1.77-17.91)] remained significantly associated with statin use. In a separate multivariate analysis, the ratio of HMGB1-to-endocan was independently associated with co-existence of CAD and NAFLD (Beta= -14.78, p<0.01). Conclusions: In patients with CAD and NAFLD, statin use is significantly associated with increased circulating angiogenic factor "endocan". On the other hand, the protective anti-endothelial IgM auto-antibody was higher in patients who had CAD without NAFLD. These endothelial cell markers may play an important role in the pathogenesis of CAD in patients with NAFLD.
AGA Abstracts
Mo1986 The Serum Indirect Bilirubin Inversely Associated With the Incidence of NAFLD Yuri Nakamura, Saeko Kasashima, Toshifumi Hara, Mikiko Fujita, Hikaru Nagahara The serum indirect bilirubin inversely associated with the incidence of NAFLD. Yuri Nakamura, Saeko Kasashima, Toshifumi Hara, Mikiko Fujita, Hikaru Nagahara Aoyama Hospital, Tokyo Women's Medical University Aim: Bilirubin has a strong anti-oxidative ability showing that the high level of serum bilirubin exhibits an inhibitory effect on diabetes mellitus. We analyzed the correlation of the serum level of indirect bilirubin (Ind-Bil) with the incidence of NAFLD, biochemical markers and anthropometric data. Materials and Methods: 862 subjects (309 female, 553 male) who underwent annual check up in our hospital on 2008 were analyzed. The subjects who were positive for hepatitis viral markers, and developed hemolytic anemia and hepatitis for next four years were excluded in this study. The subjects were divided into three groups according to the serum level of Ind-Bil; group A, Ind-Bil ^1.2mg/dl, group B, Ind-Bil 1.1~0.6mg/dl, group C, Ind-Bil%0.5mg/dl. FL was determined by the findings of echo sonography; bright liver, attenuation of echo level and liver-kidney contrast. The clinical data evaluated were as follows: gender, age, height (cm), body weight (BW; kg), waist circumference (cm), AST, ALT, γ-GTP, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglyceride (TG), high sensitivity C-reactive protein (hs-CRP), fasting blood sugar (FBS), HbA1c. Results:The incident rate of FL in three groups (%) were; 36.7% in group A, 33.1% in group B and 18% in group C (p<0.05). The serum levels of Ind-Bil were inversely correlated with waist circumference, FBS and HbA1C (p<0.05). Conclusion: The serum level of Ind-Bil inversely correlated with FL incidence, probably due to improvement of glucose metabolism.
Mo1989 A Multicenter Study for Noninvasive Characterization of Metabolic Liver Steatosis/Steatohepatitis Ignazio Grattagliano, Enzo Ubaldi, David Q. Wang, Piero Portincasa Nonalcoholic fatty liver disease (NAFLD), a worrisome health problem worldwide, is often a fellow traveller with the metabolic syndrome and a marker of increased cardiovascular risk. The necro-inflammatory form (nonalcoholic steatohepatitis, NASH) puts 5-8% of patients at risk of cryptogenic cirrhosis within 5 yrs. The ultimate diagnosis of NASH relies on liver biopsy, but noninvasive tests are actively searched for the subset of patients who will require further consultation. Fibromax® (www.biopredictive.it), for example, provided information on liver fatty infiltration, inflammation, and fibrosis. With APRI test (AST/Platelets ratio), i.e. SAFE biopsy, Fibromax screened patients with chronic liver disease candidates for liver biopsy. Aims. The performance of ultrasonography [US], fatty liver index [FLI] and Fibromax® was evaluated in NAFLD, as potential noninvasive diagnostic tool in family practice. Methods. 259 consecutive patients (165M, 94F, age 51±SD10 yrs) with clinical and ultrasonographic features of NAFLD were enrolled. Measurements included body mass index, waist circumference, semiquantitative score of liver steatosis (US), blood analyses (serum insulin, AST, ALT, total cholesterol, triglycerides, glucose, haptoglobin, bilirubin, GGT, A1-apolipoprotein, and alpha2-macroglobulin) to calculate FLI algorithm and Fibromax scores as Steatotest (0-3), NASHTest (absent, borderline, present), and Fibrotest (0-4). Results. Patients had mild (16.2%), moderate (69.9%), or severe (13.9%) liver steatosis (60.2% had hypertransaminasemia). The prevalence of overweight, obesity, diabetes, hypertension, and dyslipidemia was 42.7%, 46.5% (4.2% severe obesity), 24.7%, 40.9%, and 56.4%, respectively. Lean patients (10.8%) had normotransaminasemia in 2/3 cases. A multivariate logistic regression (including age >50 yrs, BMI>30 kg/m2, HOMA>3, and hypertransaminasemia) identified 12.3% of patients at risk for NASH. With a sensitivity of 50% and specificity of 94.7%, Fibromax identified 34 patients (13.1%) with likely advanced fibrosis and found that over 28% of patients with moderate (ultrasonographic) steatosis were likely carrying severe steatosis. Steatotest score was significantly associated with BMI, waist circumference, ALT, triglycerides, and FLI. Fibrotest correlated only with ALT. FLI identified 73.4% of patients likely carrying a fatty liver. Conclusions. NAFLD should be systematically searched and characterized in all patients with dysmetabolic stigmata and cardiovascular risk. Asymptomatic subjects at risk should also be screened for NAFLD. Fibromax is a promising noninvasive diagnostic tool, specifically in family medicine for identifying those patients at risk for NAFLD requiring targeted follow-up.
Mo1987 Angiogenic Growth Factors in Patients With Nonalcoholic Fatty Liver Disease (NAFLD) and Coronary Artery Disease Elzafir Elsheikh, Zahra Younoszai, Munkhzul Otgonsuren, Elena Younossi, Brian P. Lam, Rebecca Cable, Thomas Jeffers, Spencer Frost, Bryan Raybuck, Zobair M. Younossi Background and Aim: NAFLD is associated with arthrosclerosis and endothelial dysfunction. This pathogenic process could potentially lead to recruitment of endothelial progenitor cells (EPCs). This recruitment of EPCs from the bone marrow to homing sites (coronary artery etc.) is regulated by angiogenic growth factors (AGF). In this study we hypothesized that, angiogenic properties are impaired in NAFLD, leading to increase prevalence of coronary artery disease (CAD). Methods: We prospectively enrolled 100 patients undergoing elective coronary angiography. Each patient had fasting serum, clinical data and abdominal ultrasound. NAFLD was defined as radiologic fatty liver in the absence of other causes of liver disease and alcohol. Patients were divided into NAFLD with CAD (n=49), NAFLD without CAD (n=19), and CAD only (n=32). Each angiogram was reviewed centrally for the presence and severity of CAD (number of proximal arterial segments with>70% stenosis). We assessed serum levels of 8 angiogenic growth factors (pg/ml) (Angiopoietin-2, Bone morphogenetic protein 9 (BMP-9), fibroblast growth factor 2 (FGF-2), Granulocyte colony-stimulating factor (G-CSF), Placental growth factor (PLGF), Vascular endothelial growth factor (VEGF-A, VEGFB and VEGF-C) by Multiplex assay. Results: Of the angiogenic growth factors tested, the levels of the serum VEGF-C was higher in NAFLD patients without CAD (median, 146 pg/ ml, IQR, 58-217 pg/ml ) versus NAFLD with CAD (median, 69 pg/ml, IQR, 39-86 pg/ml) versus CAD only (median, 44 pg/ml, IQR, 36-57 pg/ml) (P=0.01and P<0.01). CAD severity was inversely associated with VEGF-C (r=-0.31; P=0.01). NAFLD patients in >75th quartile of VEGF-C levels (VEGF-C >93 pg/ml) had the lowest risk of CAD [OR: 0.23 (95% CI: 0.08-0.73)]. In multivariate analysis, VEGF-C [OR: 0.26 (95% CI: 0.08-0.87)] was protective while age [OR: 1.09 (95% CI: 1.02-1.17)] was associated with increased risk for CAD. Interestingly VEGF-C was inversely associated with ALT (r=-0.3; P=0.02) and AST (r=-0.32; P=0.01). The growth factor BMP-9 was higher in NAFLD patients without CAD (median, 75 pg/ml, IQR, 49-134 pg/ml) than CAD only (median, 49 pg/ml, IQR, 21-74 pg/ml) (P= 0.03). Conclusions: In patients with NAFLD, VEGF-C may play a protective role by affecting vessel integrity and repair.
Mo1990 Hepatic Import of Glycerol and Aquaporin-9 Are Reduced in a Murine Model of Non-Alcoholic Fatty Liver Disease Patrizia Gena, Maria Mastrodonato, Piero Portincasa, Elena Fanelli, Donatella Mentino, Amaia Rodríguez, Raúl A. Marinelli, David Q. Wang, Catherine Brenner, Gema Frühbeck, Maria Svelto, Giuseppe Calamita Non-Alcoholic Fatty Liver Disease (NAFLD), a worrisome health problem worldwide characterized by intrahepatic triacylglycerol (TG) overaccumulation, is a common feature of metabolic syndrome being often associated with obesity, dyslipidemia and diabetes and mostly closely linked to insulin resistance. Aims. Although the mechanism of NAFLD pathogenesis is intensely investigated, especially regarding complex systems resulting in excessive fat liver deposition, we aimed to investigate the relevance of hepatic import of glycerol, the other primary source (as glycerol-3-phosphate) of increased TG in hepatocytes. Methods. As animal model of NAFLD, obese leptin-deficient (ob/ob) mice were used to evaluate the functional involvement of Aquaporin-9 (AQP9), the major pathway of liver glycerol entry, in liver steatosis. Results. By real time PCR, the level of Aqp9 mRNA in the liver of starved obese mice was comparable with the corresponding control lean littermates. At level of protein, by both immunoblotting and immunohistochemistry, AQP9 at the hepatocyte sinusoidal plasma membrane of obese mice was markedly lower (33%) than lean mice. The liver glycerol permeability of ob/ob mice measured by stopped-flow light scattering was significantly lower (53%) than lean mice, a finding consistent with both the observed down-regulation of AQP9 protein and increased level of plasma glycerol characterizing obese mice. Conclusions. Overall, our results suggest relevance of AQP9 in hepatosteatosis. AQP9 down-regulation and the reduction of hepatic glycerol permeability may constitute a defensive mechanism to counteract further fat infiltration in liver parenchyma. A similar situation is seen in patients with NAFLD.
Mo1988 Factors Associated With Statins Use in Patients With Nonalcoholic Fatty Liver Disease (NAFLD) and Coronary Artery Disease (CAD) Elzafir Elsheikh, Zahra Younoszai, Munkhzul Otgonsuren, Elena Younossi, Thomas Jeffers, Spencer Frost, Bryan Raybuck, Zobair M. Younossi Background: Endocan is an angiogenic cytokine that promotes endothelial cell sprouting and migration under hypoxic conditions. Auto-antibodies may play a protective role against CAD. Statins are the most widely used medications for treatment of hyperlipidemia and prevention of cardiovascular events. Our aim was to investigate the effect of statins on the clinical, laboratory, endothelial-specific cytokine levels [endocan and High mobility group box 1 (HMGB1)] and anti-endothelial cells antibodies in NAFLD patients with and without CAD. Methods: We included patients with NAFLD with or without CAD. NAFLD was diagnosed by hepatic ultrasound or fatty liver index in the absence of any other causes of liver disease. Diagnosis and severity of CAD were established with coronary angiography. Data on current medication use including statins were obtained from the medical records. Serum endocan and HMGB1 (ng/ml) were measured by ELISA. Additionally, serum antiendothelial cells IgM and IgG auto-antibodies were measured using flow cytometry. Results: One hundred and fourteen patients were included, 43 NAFLD with CAD, 10 NAFLD without CAD, 47 CAD without NAFLD and 14 patients without CAD or NAFLD. NAFLD patients with CAD who were taking statins had higher levels of serum endocan as compared to
AGA Abstracts
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