N O T P R I N T A B L E. Plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor levels in non-alcoholic steatohepatitis

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1 J. Endocrinol. Invest. 30: , Plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor levels in non-alcoholic steatohepatitis S. Yener 1, M. Akarsu 2, T. Demir 1, B. Akinci 1, O. Sagol 3, F. Bayraktar 1, M.A. Ozcan 4, E. Tankurt 2, and S. Yesil 1 1 Division of Endocrinology and Metabolism; 2 Division of Gastroenterology, Department of Internal Medicine; 3 Department of Pathology; 4 Division of Hematology, Department of Internal Medicine, School of Medicine, Dokuz Eylul University, Izmir, Turkey Abstract. Aim: This study was conducted to demonstrate the plasminogen activator inhibitor-1 (PAI-1) and thrombin activatable fibrinolysis inhibitor antigen (TAFI-Ag) levels in non-alcoholic steatohepatitis (NASH). Materials and methods: Twenty-seven patients with biopsy-proven NASH and 18 healthy controls (HC) were recruited for the study. Anthropometric data, liver histology (no.=20) and laboratory parameters including PAI-1 and TAFI-Ag assessments were recorded. Results: When compared with HC, patients with NASH had higher body weight, higher waist circumference, elevated blood pressure, higher fasting plasma glucose (FPG) levels and higher homeostasis model assessment (HOMA) scores. The mean plasma PAI-1 levels of patients was found to be higher than HC (87.60 ng/ml vs ng/ml p=0.000) and mean plasma TAFI-Ag levels of patients was found to be significantly lower (8.69 µg/ml vs µg/ml p=0.000). PAI-1 levels were correlated with systolic blood pressure, age, body weight, transaminases, waist circumference, FPG, body mass index, and HOMA score. TAFI-Ag levels were found to be negatively correlated with transaminases, waist circumference, and body weight. In multiple regression analysis, BMI was the independent variable effecting PAI-1 levels. We did not show any association between PAI-1, TAFI-Ag, disease activity score and fibrosis score. HOMA was the independent variable effecting liver fibrosis in our patients. Conclusion: In this study we demonstrated that patients with biopsy-proven NASH had higher PAI-1 and lower TAFI-Ag expression than HC. Elevated levels of PAI-1 in NASH is the consequence of insulin resistance state. Lower TAFI-Ag levels may be related to the overactivation of TAFI pathway resulting in TAFI-Ag depletion. Furthermore, liver function disturbances may impair TAFI production in NASH. We also showed that NASH patients even with slight elevations of transaminases feature marked insulin resistance and components of metabolic syndrome. (J. Endocrinol. Invest. 30: , 2007) IntroductIon Non-alcoholic steatohepatitis (NASH), is the most severe form of non-alcoholic fatty liver disease (NAFLD). There is strong relationship between obesity, insulin resistance, and NASH and therefore the reported prevalence rates vary from 18.5% to 70% Key-words: NASH, PAI-1,TAFI. Correspondence: S. Yener, MD, Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Dokuz Eylul University, 35340, Inciralti, Izmir, Turkey. serkan.yener@deu.edu.tr, Accepted February 23, for obese patients (1-3). NASH differs from NAFLD with its characteristics such as periportal and lobular inflammation and evidence of hepatocyte injury on liver biopsy. The reason why NASH has been receiving more attention is the risk of progression to fibrosis and cirrhosis. It was previously shown that NASH is strongly associated with metabolic syndrome and the individuals are exposed to the characteristic features of the insulin resistance (4-6). In recent studies Targher et al. demonstrated that NAFLD is one of the important etiological factors for the development of early atherosclerosis. They showed that Type 2 diabetic patients in the presence of NAFLD have significant increase of carotid intima media thickness when com- 810

2 S. Yener, M. Akarsu, T. Demir, et al. J. Endocrinol. Invest. 30: , pared with Type 2 diabetic people without NAFLD (7). They also demonstrated that the prevalence of cardiovascular disease is increased in patients with Type 2 diabetes with NAFLD in association with an increased prevalence of metabolic syndrome (5). Targher et al. in a recent study demonstrated that the severity of the histological features of NAFLD independently predicted carotid intima media thickness after adjustment for all confounders (8). Hypofibrinolysis is one of the most important components of the prothrombotic state in insulin-resistant subjects and its association with premature atherosclerosis has already been demonstrated. Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of both tissue and urokinase plasminogen activator. Inhibition of plasminogen activation by PAI-1 impairs fibrinolysis and promotes thrombosis (9). PAI-1 is elevated in a variety of clinical situations that are associated with insulin resistance and increased risk of ischemic cardiovascular events such as obesity (10) and Type 2 diabetes (11). A number of cytokines that are implicated in insulin resistance such as interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α) have been found to stimulate endothelial PAI-1 production (12, 13). Furthermore PAI-1 levels were found to be related with visceral fat, blood pressure, insulin level, and atherogenic lipid profile (14). Thrombin activatable fibrinolysis inhibitor (TAFI) or carboxypeptidase U is another fibrinolysis inhibitor isolated from human plasma. TAFI is a glycoprotein synthesized by the liver that can be activated by thrombin-catalyzed proteolysis to a carboxypeptidase B like enzyme that inhibits fibrinolysis by removal of carboxy-terminal lysine and arginine residues from partly degraded fibrin polymers (15, 16). The relationship between TAFI and conditions associated with endothelial dysfunction have already been demonstrated. Kitagawa et al. demonstrated that in non-obese Type 2 diabetic people TAFI levels were associated with the degree of insulin resistance and glycemic control (11). Yano et al. demonstrated the relationship between microalbuminuria and TAFI levels in normotensive Type 2 diabetic patients (17). Obesity was also shown to increase TAFI expression (18). Table 1 - Anthropometric and laboratory characteristics of the participants (mean values are shown as ±SD). Variables NASH (no.=27) Healthy controls (no.=18) p Age (yr) 47.9± ±14.5 ns Gender (f/m) 13/14 11/7 ns Body weight (kg) 85.0± ± BMI (kg/m 2 ) 30.5± ± Waist circumference (cm) 98.3± ± SBP (mm-hg) 126.8± ± DBP (mm-hg) 80.0± ± Fasting glucose (mg/dl) 113.3± ± Fasting insulin (µiu/ml) 20.46± ± HOMA 6.20± ± ALT (U/l) 43.5± ± AST (U/l) 30.2± ± GGT (U/l) 32.3± ±12.6 ns Total cholesterol (mg/dl) 194.3± ±33.7 ns LDL-cholesterol (mg/dl) 114.7± ±28.6 ns HDL-cholesterol (mg/dl) 49.3± ±11.4 ns Triglyceride (mg/dl) 151.8± ±61.5 ns PAI-1 (ng/ml) 87.60± ± TAFI antigen (µg/ml) 8.69± ± NASH: non-alcoholic steatohepatitis; f: female; m: male; BMI: body mass index; SBP: sistolic blood pressure; DBP: diastolic blood pressure; HOMA: homeostasis model assessment; ALT: alanine transaminase; AST: aspartate transaminase; GGT: γ-glutamyl transferase; PAI-1: plasminogen activator inhibitor-1; TAFI: thrombin activatable fibrinolysis inhibitor. 811

3 J. Endocrinol. Invest. 30: , Hypofibrinolysis in NASH In the literature, TAFI levels in NASH have not been evaluated and PAI-1 levels in NASH were evaluated in only one study in which NASH diagnosis was not confirmed by liver biopsy. The objective of this study is to evaluate the levels of PAI-1 and TAFI-Antigen (TAFI-Ag) in patients with biopsy proven NASH, compare the levels with healthy controls, and demonstrate the possible relations between PAI-1, TAFI-Ag, disease activity and fibrosis. Materials and Methods Subjects Twenty-seven patients (14 male, mean age: 47.9) with biopsyproven NASH and 18 healthy controls (7 male, mean age: 42.7) were recruited for the study. Diagnosis of NASH was confirmed with the histological examination of percutaneous liver biopsies. They had history of raised alanine aminotransferase (ALT) levels 95% CI (1.5 times higher than normal values for 6 months or more) and steatosis at ultrasound scan. The patients did not have history of alcohol consumption exceeding 20 g/day. Other possible causes of chronic liver diseases like viral hepatitis, autoimmune hepatitis or primary biliary cirrhosis, Wilson Disease, hemochromatosis were excluded with appropriate laboratory investigations and liver biopsies were then performed. In the NASH group all of the patients were being treated with low-calorie and low-fat diet. Nine patients had Type 2 diabetes; 5 of them were on metformin and 2 of them were on insulin therapy. Age- and gender-matched healthy controls without any known diseases were enrolled. In the patients group, 7 patients liver biopsies were excluded from pathological revision to maintain a standardised examination. An experienced hepatopathologist blinded to the remaining 20 patients clinical status examined liver biopsy specimens and scored using the novel classification defined by Kleiner and Brunt (19). Basically, the diagnosis of NASH is based on NAFLD activity score (NAS) 5. NAS is defined to be the sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. NAS is also p= p= no.= NASH HC PAI-1 (ng/ml) TAFI-Ag (µg/dl) Fig. 1 - Error bars representing the mean plasminogen activator inhibitor-1 (PAI-1) and thrombin activatable fibrinolysis inhibitor antigen (TAFI-Ag) levels in patients and healthy controls (HC). CI: confidence interval; NASH: of non-alcoholic steatohepatitis. 812

4 S. Yener, M. Akarsu, T. Demir, et al. J. Endocrinol. Invest. 30: , used to determine the disease activity. Fibrosis is evaluated separately from NAS and is graded from 0 (no fibrosis) to 4 (cirrhosis). Exclusion criteria were, (a) subjects aged >75 yr or <18 yr; (b) subjects with alcohol consumption >20 g/day; (c) subjects who had a recent history of acute illness or infectious disease; (d) subjects who had history of cardiovascular, cerebrovascular, kidney or malignant disease, coagulation disorders, and severe systemic diseases; (e) subjects with angina pectoris, claudicatio intermittens, abnormal resting electrocardiography or treadmill exercise test; (f) subjects receiving anti-coagulation drugs; (g) subjects using oral contraceptives or hormonal replacement therapy; and (h) pregnant women or women of child-bearing potential. All participants gave their written informed consent and the study protocol was approved by local Ethics Committee. Methods Height (m), weight (kg), waist circumference (WC) (cm) were measured under fasting conditions with subjects in light clothing and without shoes. All measurements were taken with the subject standing upright. Body mass index (BMI) was calculated as body weight divided by square height. Blood pressure was measured using a sphygmomanometer in the sitting position after 5 min resting. Fasting blood samples for glucose, fasting insulin, alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyl transferase (GGT), total cholesterol, HDL-cholesterol (HDL-C), triglyceride, PAI-1, and TAFI-Ag assessments were obtained between 08:00 am and 09:00 am from the cannulated antecubital vein. For PAI-1 and TAFI-Ag assessments platelet-poor plasma was obtained by centrifugation at 2000 bpm for 15 min at 4 C. The plasma samples were stored at 80 C. TAFI-Ag levels and PAI-1 levels were measured using enzyme-linked immunosorbent assay (ELISA) kits (TAFI-Ag; Affinity Biologicals; Ontario, Canada and PAI-1; American Diagnostica; Sanford, US). Fasting plasma glucose (FPG), transaminases, GGT, total cholesterol, HDL-C, triglyceride were measured by Roche/Hitachi D/P Modular System Autoanalyzer (Roche Diagnostics, Basel, Switzerland). Insulin was measured using chemiluminescence enzyme immunoassay kits (Immunolite, Diagnostic Products Corporation, Los Angeles, USA). LDL-cholesterol (LDL-C) was calculated. For PAI-1 the intraassay coefficient of variation is 4% and the interassay coefficients of variation is 4.3%. For TAFI-Ag the intraassay and interassay coefficient of variation is 6%. The degree of insulin resistance was calculated from the homeostasis model assessment (HOMA) (20). Table 2 - Anthropometric and laboratory data of non-alcoholic steatohepatitis (NASH) patients after grouping for the presence of Type 2 diabetes. Variables DM+NASH (no.=9) DM NASH (no.=18) Healthy controls (no.=18) Age (yr) 53.5± ± ±14.5 Gender (f/m) 5/4 8/10 11/7 Body weight (kg) 82.2±13.3 &&& 86.2± ±14.2 BMI (kg/m 2 ) 30.9±13.8 ### 30.3± ±4.0 Waist circumference (cm) 99.2±7.2 # 97.9± ±16.7 SBP (mm-hg) 131.6± ± ±7.5 DBP (mm-hg) 80.0± ± ±8.4 Fasting glucose (mg/dl) 138.6±43.1 ### 100.8±26.7* && 87.5±8.7 Fasting insulin (µiu/ml) 30.2±16.5 ### 15.5±12.4* 7.89±4.35 HOMA 10.6±7.3 ### 4.1±3.3* 1.71±0.97 ALT (U/l) 33.5±11.4 # 50.8± ±11.1 AST (U/l) 28.3±7.0 ## 31.8± ±5.8 GGT 32.0± ± ±12.6 Total cholesterol (mg/dl) 195.1± ± ±33.7 LDL-cholesterol (mg/dl) 116.3± ± ±28.6 HDL-cholesterol (mg/dl) 43.5± ± ±11.4 Triglyceride (mg/dl) 176.0± ± ±61.5 PAI-1 (ng/ml) ±23.46 ### 79.20±41.52 & 30.84±10.73 TAFI Antigen (µg/ml) 9.36±2.83 # 8.36± ±2.65 DM+NASH: Type 2 diabetics (DM) with NASH; DM NASH: DM without NASH; f: female; m: male; BMI: body mass index; SBP: sistolic blood pressure; DBP: diastolic blood pressure; HOMA: homeostasis model assessment; ALT: alanine transaminase; AST: aspartate transaminase; GGT: γ-glutamyl transferase; PAI-1: plasminogen activator inhibitor-1; TAFI: thrombin activatable fibrinolysis inhibitor. & p=0.059 DM+NASH vs DM NASH, *p<0.005 DM+NASH vs DM NASH, && p=0.053 DM NASH vs healthy controls (HC), p DM NASH vs HC, p<0.001 DM NASH vs HC, &&& p=0.064 DM+NASH vs HC, # p<0.05 DM+NASH vs HC, ## p<0.01 and ### p DM+NASH vs HC 813

5 J. Endocrinol. Invest. 30: , Hypofibrinolysis in NASH Statistical analysis Data were analyzed using test by the Statistical Package for the Social Sciences 11.0 for Windows software. Non-parametric tests were conducted by using Mann-Whitney U, Kruskal Wallis-H and Spearman correlation analyses and statistical significance was accepted at p<0.05. RESULTS A group of 27 patients with liver biopsy proven NASH and 18 healthy controls were recruited for the study. There was no significant difference for gender and age between the 2 groups. Compared with controls, patients with NASH had higher body weight (85.0 kg vs 70.6 kg, p=0.02), higher BMI (30.5 kg/m 2 vs 24.3 kg/m 2, p=0.000), higher WC (98.3 cm vs 81.6 cm, p=0.002), elevated sistolic and diastolic blood pressures (SBP and DBP) (126.8 vs and 80.0 vs 73.3 p=0.016 and p=0.039, respectively), higher FPG levels (113.3 mg/dl vs 87.5 mg/dl p=0.002), higher fasting insulin levels (20.4 vs 7.8 p=0.000), higher HOMA scores (6.2 vs 1.7), higher levels of ALT and AST (43.5 U/l vs 21.0 U/l p=0.01 and 30.2 U/l vs 19.2 U/l p=0.004, respectively) and higher but not significant levels of GGT (32.3 U/l vs 23.1 U/l p=0.279). No significant difference was determined 140 for the lipid parameters between the 2 groups. The mean plasma PAI-1 levels of patients was found to be higher than healthy controls (87.60 ng/ml vs ng/ml p=0.000) and mean plasma TAFI-Ag levels were significantly lower than healthy controls (8.69 µg/ml vs µg/ml p=0.000). The anthropometric and laboratory data of the patients are summarised in Table 1. PAI-1 and TAFI-Ag levels in groups are shown in Figure 1. Nine of the 27 patients with NASH had Type 2 diabetes. The anthropometric and laboratory data of the Type 2 diabetics (DM) with NASH DM+NASH and without NASH DM NASH are reported in Table 2. Plasma PAI-1 and TAFI-Ag levels for DM+NASH, DM NASH, and healthy controls are shown in Figure 2. Age, gender, SBP, DBP, and levels of lipid parameters did not differ between groups. BMI was highest in DM+NASH group and also significantly elevated in DM NASH group compared with controls. FPG, fasting insulin, and HOMA scores were highest in DM+NASH group and significantly higher than healthy controls in DM NASH group. Plasma PAI-1 levels were found to be highest in DM+NASH group and also DM NASH group has significant elevated levels of PAI-1 compared with healthy controls. Plasma TAFI-Ag levels are higher in p=0.059 p= % CI p= p= p=0.031 p= no.= DM+NASH DM NASH HC PAI-1 (ng/ml) TAFI-Ag (µg/dl) Fig. 2 - Plasma plasminogen activator inhibitor-1 (PAI-1) and thrombin activatable fibrinolysis inhibitor antigen (TAFI-Ag) levels in Type 2 diabetics (DM) with non-alcoholic steatohepatitis (NASH) (DM+NASH), DM without NASH (DM NASH), and healthy controls (HC). CI: confidence interval. 814

6 S. Yener, M. Akarsu, T. Demir, et al. J. Endocrinol. Invest. 30: , Table 3 - Anthropometric and laboratory data of non-alcoholic steatohepatitis (NASH) patients after grouping for the presence of fibrosis. Variables NASH-F+ (no.=10) NASH-F (no.=10) Age (yr) 50.9± ±8.0 Gender (f/m) 3/7 5/5 Body weight (kg) 85.3± ±10.9 BMI (kg/m 2 ) 31.7± ±6.8 Waist circumference (cm) 97.8± ±7.8 SBP (mm-hg) 135.0± ±11.8 DBP (mm-hg) 85.0± ±7.8 Fasting glucose (mg/dl) 124.9±33.5* 90.8±14.4 Fasting insulin (µiu/ml) 23.5± ±7.9 HOMA 7.5±5.5 $ 2.9±1.5 ALT (U/l) 48.2± ±8.4 AST (U/l) 33.8± ±4.7 GGT 37.4± ±26.8 Total cholesterol (mg/dl) 195.2± ±49.0 LDL-cholesterol (mg/dl) 115.8± ±43.1 HDL-cholesterol (mg/dl) 50.2± ±15.5 Triglyceride (mg/dl) 145.7± ±51.1 PAI-1 (ng/ml) 90.71± ±37.94 TAFI Antigen (µg/ml) 9.28± ±3.13 NASH-F+: NASH+fibrosis; NASH-F : NASH fibrosis; f: female; m: male; BMI: body mass index; SBP: sistolic blood pressure; DBP: diastolic blood pressure; HOMA: homeostasis model assessment; ALT: alanine transaminase; AST: aspartate transaminase; GGT: γ-glutamyl transferase; PAI-1: plasminogen activator inhibitor-1; TAFI: thrombin activatable fibrinolysis inhibitor. For p-values * 0.001, $ <0.01 and =0.075 healthy controls than in DM+NASH, and the lowest values for TAFI-Ag were found in DM NASH group. The mean NAS of the eligible 20 patients was found to be 5.7±1.3. Fibrosis was found to be present in 10 patients (50%). When the patients were divided into 2 groups based on the presence of fibrosis (NASH-F+ vs NASH-F ) it was found that FPG and HOMA scores were significantly higher in NASH-F+ group. None of the other anthropometric and laboratory parameters including PAI-1 and TAFI-Ag were different between groups (Table 3). Non-parametric correlation analysis demonstrated that PAI-1 levels were correlated with SBP (r=0.332, p=0.026), age (r=0.343, p=0.025), body weight (r=0.356, p=0.021), AST (r=0.370, p=0.032), WC (r=0.479, p=0.002), ALT (r=0.494, p=0.001), FPG (r=0.547, p=0.000), BMI (r=0.554, p=0.000), fasting insulin (r=0.559, p=0.000), and HOMA score (r=0.574, p=0.000). TAFI-Ag levels were found to be negatively correlated with AST (r= 0.315, p=0.042), WC (r= 0.364, p=0.005), ALT (r= 0.364, p=0.045), and body weight (r= 0.428, p=0.005). In multiple regression analysis after adjustment for HOMA, BMI, age, SBP, and ALT, BMI remained as the independent variable effecting PAI-1 levels. In regression analysis none of the variables were shown to have independent effects on TAFI-Ag levels after adjustment for HOMA, PAI-1, BMI, age, SBP, and ALT (Table 4). There was no association between PAI-1, TAFI-Ag, NAS, and fibrosis score in NASH patients. None of the variables were found to effect NAS. SBP, DBP, FPG, fasting insulin, ALT, AST, and HOMA score were found to be associated with fibrosis. In multiple regression analysis after adjustment for BMI, WC, SBP, DBP, AST, ALT, HOMA score, PAI-1 and TAFI-Ag, HOMA score was found to be the independent variable effecting fibrosis scores. DISCUSSION In this study we have shown for the first time that patients with biopsy-proven NASH have higher levels of PAI-1 and lower levels of TAFI-Ag compared with healthy controls. We found that Type 2 diabetic NASH patients have higher levels of PAI-1 than nondiabetic NASH patients and non-diabetic NASH patients have significant elevated levels of PAI-1 compared with healthy controls, demonstrating the role of insulin resistance for PAI-1 over-expression. Low TAFI-Ag levels in NASH may be a result of depletion due to TAFI pathway activation. Besides, liver function disturbances may cause reductions in hepatic TAFI production. We did not find any relations between PAI-1, TAFI, NAS, and fibrosis scores. Our results noticed hyperinsulinism as the independent variable effecting liver fibrosis. In the literature it was demonstrated that patients with NASH have components of metabolic syndrome (5, 6). Our results are consistent with these findings. We found that patients with NASH had higher body weight, BMI, and WC compared to age- and gender-matched healthy controls demonstrating the increased visceral fat accumulation. The mean SBP and DBP of patients were found to be significantly elevated. In the patients group mean values of SBP and DBP were in acceptable ranges (126.8±15.0 vs 80.0±10.0, respectively) but as blood pressure is a continuous variable this difference between patients and healthy controls should be taken into consideration as a risk factor for developing early atherosclerosis. We demonstrated elevated levels of FPG, fasting insulin and HOMA score in NASH patients as a consequence of the insulin resistant state. The fibrosis score was found 815

7 J. Endocrinol. Invest. 30: , Hypofibrinolysis in NASH Table 4 - Linear correlations of thrombin activatable fibrinolysis inhibitor antigen (TAFI-Ag), plasminogen activator inhibitor-1 (PAI-1), fibrosis score, and non-alcoholic fatty liver disease activity score (NAS) with anthropometric and laboratory variables in the whole sample [for p-values *=0.053, **<0.05, 0.005, 0.001, p independent variable for PAI-1 after adjustment for homeostasis model assessment (HOMA), body mass index (BMI), age, sistolic blood pressure (SBP) and alanine transaminase (ALT); β=.405 p=0.048] and F independent variable for fibrosis after adjustment for BMI, waist circumference, SBP, diastolic blood pressure (DBP), aspartate transaminase (AST), ALT, HOMA score, PAI-1 and TAFI-Ag. Variables PAI-1 TAFI-Ag Fibrosis NAS Age 0.343** Body weight 0.356** BMI 0.554, p Waist circumference ** SBP 0.332** ** DBP * FPG Fasting insulin ** HOMA , F ALT ** AST 0.370** 0.315** 0.571** GGT Total cholesterol LDL-cholesterol HDL-cholesterol Triglyceride PAI TAFI-Ag NAS Fibrosis score FPG: fasting plasma glucose; GGT: γ-glutamyl transferase. to be effected by several metabolic syndrome components and, besides, we found HOMA score as the independent factor for liver fibrosis (Table 4). The data on the mechanisms of fibrosis in NASH has been assumed to be related with several cytokines and oxidative stress. Fibrogenic growth factor, connective tissue growth factor, leptin, and especially transforming growth factor-β1 (TGF-β1) were found to be elevated in NASH and their levels (especially TGF-β1) were shown to be associated with the degree of insulin resistance. It is suggested that these cytokines promote fibrogenesis in hepatocytes (21). The primary objective of our study was to demonstrate the hypofibrinolytic state in NASH. We demonstrated that patients with NASH had higher PAI-1 expression than healthy people. It is now well established that hypofibrinolysis due to elevated plasma PAI-1 levels is a key feature of the insulin resistance syndrome (22). In the literature PAI-1 levels in fatty liver was studied in NAFLD diagnosed by radiologic interventions. Bruckert et al. demonstrated a significant and independent correlation between PAI-1 and the concentration of GGT, AST, and ALT (23). Cigolini et al. showed that liver steatosis evaluated by ultrasonography correlates specifically with increased PAI-1 levels (24). Ishii et al. showed that in non- to mild obese Type 2 diabetic people liver fat content measured by magnetic resonance spectroscopy is independently associated with PAI-1 levels (25). A recent study by Targher et al. evaluated the PAI-1 activity in patients with NAFLD. In their study PAI-1 activity was found to be higher than healthy controls and also plasma triglycerides and HOMA insulin resistance score were demonstrated as the independent variables predicting PAI-1 activity (26). The authors emphasized that the lack of liver biopsies 816

8 S. Yener, M. Akarsu, T. Demir, et al. J. Endocrinol. Invest. 30: , ** ** 15 * * 80 PAI TAFI-Ag NASH-F+ NASH-F HC NASH-F+ NASH-F HC Fig. 3 - Plasma plasminogen activator inhibitor-1 (PAI-1) and thrombin activatable fibrinolysis inhibitor antigen (TAFI-Ag) levels in NASH+fibrosis (NASH-F+), NASH fibrosis NASH-F and healthy controls (HC) groups (for p-values *, p<0.05 vs HC and **, p=0.000 vs HC). 0 for the diagnosis of NAFLD is a limitation for their study. In our study, patients with liver biopsy proven NASH were included to overcome such a limitation. We also showed that the degree of insulin resistance is strongly correlated with PAI-1 expression as Type 2 diabetic patients with NASH had highest PAI-1 levels and non-diabetic NASH patients had significantly elevated levels of PAI-1 when compared with healthy people. Strong associations found between PAI-1, BMI, FPG, fasting insulin, and HOMA score support the literature. As Alessi noticed there is a vicious circle between PAI-1 and metabolic syndrome, that PAI-1 overexpression is both a cause of the metabolic syndrome and also a consequence of the hyperinsulinemic state (14). Visceral obesity, adipocytokines such as TNF-α and TGF-β, the alteration in renin-angiotensin system and oxidative stress are responsible for PAI-1 elevation seen in metabolic syndrome. Despite the marked correlations between PAI-1, ALT, and AST, we did not find any association between disease activity score, fibrosis, and PAI-1. This finding is not easy to explain. We demonstrated strong correlations between PAI-1 and HOMA score and also fibrosis score and HOMA. Furthermore PAI-1 level of NASH-F+ patients is found to be higher (but ns) than NASH-F group (90.71 ng/ml vs ng/ml) (Fig. 3). We suggest that the lack of an association between histologic findings and PAI-1 might be the consequence of the small study group. In the literature TAFI-Ag and TAFI-activity measurements and its relations with metabolic syndrome components are not well defined when compared with studies evaluating PAI-1. In a small number of studies Type 2 diabetic patients were demonstrated to have higher TAFI levels compared with healthy controls and the degree of insulin resistance was demonstrated to be correlated with TAFI-Ag levels and TAFI activity (27). Aso et al. demonstrated that plasma TAFI levels were positively correlated with total and LDL-C and high sensitive C-reactive protein (hscrp) (28). In their study no significant association was found between TAFI and metabolic syndrome components. In the literature neither TAFI-Ag nor TAFI activity have been studied in NAFLD or NASH. We demonstrated that patients with NASH have significantly lower levels of TAFI-Ag compared with healthy controls. Altered liver functions during the course of NASH could be responsible for decreased TAFI production as liver is suggested to be the main production site of TAFI (29). The important role of the liver for TAFI production was demonstrated in patients with chronic liver diseases and cirrhosis (30-32). In our study another finding supporting the role of liver function disturbances for the decreased levels of TAFI-Ag was the significant negative correlation between TAFI-Ag and transaminases. However, there is concern on this hypothesis as we did not show any relation between TAFI-Ag and NAS or fibrosis score. Another possible explanation for low levels of TAFI-Ag in NASH patients may be a reduction secondary to activated TAFI pathway. In the literature decreased TAFI-Ag levels were found to be correlated with activation of some coagulation factors such as prothrombin in patients with sepsis (33). Zorio et al. reported low TAFI-Ag levels but significantly elevated TAFI activity in young patients with myocardial infarction. In this study plasma PAI-1 antigen levels and activity were found to be correlated with TAFI activity. They also found a positive relationship between TAFI activity and activation of protein C system. They suggested that lower TAFI-Ag levels in these patients are associated with overactivation of TAFI pathway, resulting in hypofibrinolysis. Similarly, elevated PAI-1 and decreased TAFI-Ag levels in NASH patients could suggest that decreased TAFI-Ag levels might be related to the activation of TAFI pathway. In our study, in spite of the slight elevations in transaminase levels (mean ALT: 43.5 and mean AST: 30.2) and the relatively low mean NAS score (5.7), 817

9 J. Endocrinol. Invest. 30: , Hypofibrinolysis in NASH NASH patients were shown to feature marked hyperinsulinism and related disturbances such as PAI-1 elevation. In the literature, studies evaluating NAFLD generally included patients with marked elevations in transaminase levels. Our finding demonstrates that even with slight disturbances in liver functions NASH may lead to serious metabolic disturbances. Our study has several limitations. The major limitation is its small sample size. In addition, as parameters of hypofibrinolysis have importance especially during the development of early atherosclerosis this study might include additional investigations such as demonstrating flow mediated dilatation. In conclusion, we showed elevated PAI-1 expression that is associated with the degree of insulin resistance in biopsy proven NASH patients. PAI-1 levels were not associated with the grade of steatohepatitis or fibrosis. In addition, TAFI-Ag levels were found to be low in NASH patients suggesting the overactivation of TAFI pathway resulting in TAFI-Ag depletion. Another possible hypothesis is the role of liver disturbance, as liver is the main source of TAFI-Ag production. But this approach has some concerns as we did not show any relations between liver histology and TAFI-Ag. In our patients insulin resistance was shown to be the independent factor effecting liver fibrosis in NASH. REFERENCES 1. Dixon JB, Bhathal PS, O Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001, 121: Garcia-Monzon C, Martin-Perez E, Iacono OL, et al. Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated with obesity. J Hepatol 2000, 33: Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. 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Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk. J Thromb Haemost 2003, 1: Kitagawa N, Yano Y, Gabazza EC, et al. Different metabolic correlations of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 in non-obese type 2 diabetic patients. Diabetes Res Clin Pract 2006, 73: Emeis JJ, Kooistra T. Interleukin 1 and lipopolysaccharide induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells. J Exp Med 1986, 163: Sawdey M, Podor TJ, Loskutoff DJ. Regulation of type 1 plasminogen activator inhibitor gene expression in cultured bovine aortic endothelial cells. Induction by transforming growth factor-beta, lipopolysaccharide, and tumor necrosis factor-alpha. J Biol Chem 1989, 264: Alessi MC, Juhan-Vague I. PAI-1 and the metabolic syndrome: links, causes, and consequences. Arterioscler Thromb Vasc Biol 2006, 26: Wang W, Boffa MB, Bajzar L, Walker JB, Nesheim ME. 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10 S. Yener, M. Akarsu, T. Demir, et al. J. Endocrinol. Invest. 30: , Cigolini M, Targher G, Agostino G, Tonoli M, Muggeo M, De Sandre G. Liver steatosis and its relation to plasma haemostatic factors in apparently healthy men--role of the metabolic syndrome. Thromb Haemost 1996, 76: Ishii M, Yoshioka Y, Ishida W, et al. Liver fat content measured by magnetic resonance spectroscopy at 3.0 tesla independently correlates with plasminogen activator inhibitor-1 and body mass index in type 2 diabetic subjects. Tohoku J Exp Med 2005, 206: Targher G, Bertolini L, Scala L, Zoppini G, Zenari L, Falezza G. Non-alcoholic hepatic steatosis and its relation to increased plasma biomarkers of inflammation and endothelial dysfunction in non-diabetic men. Role of visceral adipose tissue. Diabet Med 2005, 22: Hori Y, Gabazza EC, Yano Y, et al. Insulin resistance is associated with increased circulating level of thrombin-activatable fibrinolysis inhibitor in type 2 diabetic patients. J Clin Endocrinol Metab 2002, 87: Aso Y, Wakabayashi S, Yamamoto R, Matsutomo R, Takebayashi K, Inukai T. Metabolic syndrome accompanied by hypercholesterolemia is strongly associated with proinflammatory state and impairment of fibrinolysis in patients with type 2 diabetes: synergistic effects of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor. Diabetes Care 2005, 28: Eaton DL, Malloy BE, Tsai SP, Henzel W, Drayna D. Isolation, molecular cloning, and partial characterization of a novel carboxypeptidase B from human plasma. J Biol Chem 1991, 266: Colucci M, Binetti BM, Branca MG, et al. Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis. Hepatology 2003, 38: Lisman T, Leebeek FW, Mosnier LO, et al. Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis. Gastroenterology 2001, 121: Van Thiel DH, George M, Fareed J. Low levels of thrombin activatable fibrinolysis inhibitor (TAFI) in patients with chronic liver disease. Thromb Haemost 2001, 85: Zeerleder S, Schroeder V, Hack CE, Kohler HP, Wuillemin WA. TAFI and PAI-1 levels in human sepsis. Thromb Res 2006, 118:

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