S. Francque

Visceral adiposity and insulin resistance are independent predictors of the presence of non-cirrhotic NAFLD-related portal hypertension

Introduction:We previously demonstrated in an animal model that steatosis, in the absence of fibrosis, induces a significant rise in portal pressure, indicating substantial changes in liver hemodynamics. As assessment of portal pressure is an invasive procedure, non-invasive parameters are needed to identify patients at risk.Aims:To study the portal pressure in nonalcoholic fatty liver disease patients and to identify factors that are possibly related to steatosis-induced changes in liver hemodynamics.Materials and methods:Patients presenting with a problem of overweight or obesity, and in whom non-invasive investigations showed signs of liver involvement, were proposed for transjugular hepatic vein catheterization and liver biopsy. The biopsy was scored according to the Nonalcoholic Steatohepatitis Clinical Research Network Scoring System.Results:A total of 50 consecutive patients were studied. Their mean age was 47.9±1.8 years; 31 (62%) were female. Hepatic venous pressure gradient was normal in 36 (72%) and elevated in 14 (28%) patients. The degree of steatosis was the only histological parameter that differed significantly between the two groups (P=0.016), and was a predictor of the presence of portal hypertension (PHT) in regression analysis (P=0.010). Comparing normal versus portal hypertensive patients, waist circumference (117±2 versus 128±4 cm, P=0.005), waist–hip ratio (0.96±0.06 versus 1.04±0.03, P=0.003), visceral fat (229±15 versus 292±35 cm2, P=0.022), fasting insulin (15.4±1.7 versus 21.8±2.4 μU ml−1, P=0.032), fasting c-peptide (1.22±0.06 versus 1.49±0.09 nmol l−1, P=0.035) and homeostasis model assessment–insulin resistance (HOMA IR) (3.28±0.29 versus 4.81±0.57, P=0.019) were significantly higher. Age, gender, liver enzymes, ferritin and high-sensitive C-reactive protein were not significantly different. In regression analysis, waist circumference (P=0.008) and HOMA IR (P=0.043) were independent predictors of PHT.Conclusions:Estimates of both visceral adiposity and IR are predictors for the presence of PHT, related to the degree of steatosis, and may help in identifying patients who are at risk of developing steatosis-related complications.

Peripheral and Hepatic Vein Cytokine Levels in Correlation with Non-Alcoholic Fatty Liver Disease (NAFLD)-Related Metabolic, Histological, and Haemodynamic Features

Background Haemodynamic impairment, inflammatory mediators and glucose metabolism disturbances have been implicated in the pathogenesis of Non-Alcoholic Fatty Liver Disease (NAFLD). Aim To investigate the cytokine profile in NAFLD patients in peripheral (P) and hepatic venous (HV) blood and to compare with histology, haemodynamic and metabolic parameters. Methods 40 obese patients with an indication for a transjugular liver biopsy were enrolled. Besides an extended liver and metabolic work-up, interleukin (IL) 1B, IL4, IL6, IL10, IL23, tumour necrosis factor (TNF) α and interferon (INF) γ were measured in plasma obtained from P and HV blood by means of multiplex immunoassay. The T helper (Th)1/Th2, the macrophage M1/M2 and the IL10/IL17a ratios were calculated. Results A decrease of the P-IL10/IL17-ratio and an increase of the P-M1/M2-ratio (p<0.05) were observed in NASH versus no-NASH patients. A P-M1/M2-ratio increase was detected also in patients with portal hypertension in comparison with patients without it (p<0.05). Moreover diabetic patients showed an increase of the P-Th1/Th2-ratio in comparison with non-diabetic ones (p<0.05). The P-M1/M2 ratio positively correlated with steatosis grade (r = 0.39, p = 0.02) and insulin (r = 0.47, p = 0.003). The HV-M1/M2 ratio positively correlated with fasting insulin and Hepatic Venous Pressure Gradient (r = 0.47, p = 0.003). IL6 correlated with the visceral fat amount (r = 0.36, p = 0.02). The P- and HV-IL10/IL17 ratios negatively correlated with fasting insulin (respectively r = -0.4, p = 0.005 and r = 0.4, p = 0.01). Conclusions A proinflammatory cytokine state is associated with more disturbed metabolic, histological, and haemodynamic features in NAFLD obese patients. An increase of the M1/M2 ratio and a decrease of the IL10/IL17 ratio play a key role in this process.

Chronic hepatitis and other liver disease

PART 1 - THE SCOPE OF PUBLIC HEALTH 1. The development of the discipline of public health 2. Determinants of health and disease 3. Public health policies 4. Law, ethics, and challenges PART 2 - THE METHODS OF PUBLIC HEALTH 5. Information systems and sources of intelligence 6. Epidemiologic and biostatistical approaches 7. Social Science techniques 8. Environmental and occupational health sciences PART 3 - THE PRACTICE OF PUBLIC HEALTH 9. Major health problems 10. Prevention and control of public health hazards 11. Intervention for special populations 12. Public health functions

1374 ANA POSITIVITY IDENTIFIES A SUBGROUP OF NAFLD PATIENTS WITH DISTINCT METABOLIC PROFILE AND IMPAIRED HISTOLOGICAL RESPONSE TO WEIGHT LOSS

normal liver enzymes in the treatment group, or the possibility to undergo phlebotomy in the controls. Nevertheless, in a per-protocol analysis of patients who completed the study, amelioration of histological damage was demonstrated in 7/11 (64%) phlebotomized patients vs. 1/8 (12%) controls (p = 0.026). Conclusions: Phlebotomy is well tolerated in patients with NAFLD and increased iron stores, effectively reduces iron stores, and results in an improvement in ALT and AST levels. These preliminary results suggest that iron depletion may possibly improve liver damage in patients with NAFLD and increased iron stores.

76 THE EFFECT OF WEIGHT LOSS ON NONALCOHOLIC FATTY LIVER DISEASE IN AN OVERWEIGHT AND OBESE POPULATION

Background and Aims: Nonalcoholic steatohepatitis (NASH) is a serious public health problem. There is currently a lack of effective treatments and noninvasive diagnostic markers. We have recently demonstrated that hepatocyte-derived microparticles (MPs) are critical signals that contribute to angiogenesis and liver damage in NASH (Presidential Plenary AASLD 2012). Here we tested the hypothesis that circulating hepatocyte-MPs are novel targets for noninvasive monitoring of NASH. Methods: Male C57BL/6 mice were placed on Choline Deficient L-Amino Acid (CDAA) diet, Choline Supplemented L-Amino Acid (CSAA) or regular Chow diet for 4 and 20 weeks. These time points were chosen as they have been shown to be associated with early stage and established NASH, respectively. Circulating MPs were isolated from platelet-free plasma (PFP), detected by flow cytometry and extensively characterized by electron microscopy in liver tissue and circulation, dynamic light scattering and by LC MS/MS proteomic analysis. Liver specimens were collected and used for histological, biochemical, and molecular analysis of steatosis, inflammation, angiogenesis, fibrosis and cell death. Results: A marked increased in circulating levels of MPs were detected in mice with established NASH (20wks CDAA diet: 304,400 MPs/mL vs. 20 wks CSAA 34,300 MPs/mL vs. Chow 2,000 MPs/mL, p < 0.0052). The increase was time-dependent and the levels of MPs in blood strongly correlated with histological features of liver damage in particular with fibrosis as determined by morphologic quantification of Sirius Red staining (r = 0.736; p< 0.0002) and cell death determined by TUNEL assay (r = 0.804; p < 0.0001). We next characterized the antigenic composition of circulating MPs using a comprehensive proteomic approach by LC-MS/MS analysis. A gene ontology analysis of the proteins identified 26.5% plasma membrane proteins, 58.8% cytoplasmic proteins, 8.8% nuclear proteins and 5.9% extracellular proteins. Analysis of the molecular function of these proteins demonstrated that 35.3% were enzymes, 41.2% were cytoskeleton or vesiculation proteins, 2.9% protein of the nucleosome and 5.9% ribonucleoproteins. Conclusion: Our data identified circulating MPs with a unique antigenic composition as potential novel biomarkers for noninvasive diagnosis of NASH.

1329 CORRELATION OF NORMAL VERSUS ELEVATED ALT AND GGT IN AN OBESE POPULATION, ASSOCIATION WITH LIVER HISTOLOGY AND METABOLIC PARAMETERS

1329 CORRELATION OF NORMAL VERSUS ELEVATED ALT AND GGT IN AN OBESE POPULATION, ASSOCIATION WITH LIVER HISTOLOGY AND METABOLIC PARAMETERS A. Verrijken, S. Francque, I. Mertens, M. Ruppert, G. Hubens, E. Van Marck, P. Michielsen, L. Van Gaal. Endocrinology, Diabetology and Metabolic Diseases, Gastroenterology and Hepatology, Abdominal Surgery, Pathology, Antwerp University Hospital, Antwerp, Belgium E-mail: an.verrijken@uza.be

339 NAFLD LIVER FAT SCORE STRONGLY CORRELATES WITH HISTOLOGICAL SEVERITY OF NAFLD AND NASH IN A LARGE COHORT OF PROSPECTIVELY INCLUDED OVERWEIGHT PATIENTS

339 NAFLD LIVER FAT SCORE STRONGLY CORRELATES WITH HISTOLOGICAL SEVERITY OF NAFLD AND NASH IN A LARGE COHORT OF PROSPECTIVELY INCLUDED OVERWEIGHT PATIENTS S. Francque, A. Verrijken, I. Mertens, G. Hubens, E. Van Marck, P. Michielsen, L. Van Gaal. Department of Gastroenterology Hepatology, Department of Endocrinology, Diabetology and Metabolism, Department of Abdominal Surgery, Department of Pathology, Antwerp University Hospital, Edegem, Belgium E-mail: sven.francque@uza.be