Circulating Adropin and Preptin In Non-Alcoholic Steatohepatitis and Their Relationship with Carotid Intima Media Thickness

Circulating Adropin and Preptin In Non-Alcoholic Steatohepatitis and Their Relationship with Carotid Intima Media Thickness | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Circulating Adropin and Preptin In Non-Alcoholic Steatohepatitis and Their Relationship with Carotid Intima Media Thickness Banu Demet Coskun, Oguzhan Dizdar, Isıl Cakır, Ali Koc This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7279629/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 10 You are reading this latest preprint version Abstract Background Adropin and preptin are recently identified as peptide hormones that act as potential mediators between metabolic dysfunction and vascular injury. However, their clinical relevance in non-alcoholic steatohepatitis (NASH) remains unclear. Thus, we aimed to evaluate serum adropin and preptin levels and their association with carotid intima-media thickness (CIMT) in patients with biopsy-proven NASH. Methods This cross-sectional study included 40 patients with histologically proven NASH and 30 age- and sex-matched healthy controls. This study enrolled 40 NASH patients and 30 healthy controls. None of the participants had diabetes, hypertension, or hyperlipidemia. Anthropometric, biochemical measurements and doppler ultrasonography were performed. Results Serum adropin and preptin levels were significantly lower in NASH patients compared to controls (p = 0.02 and p = 0.03, respectively). Adropin levels were significantly negatively correlated with body mass index (BMI), body fat mass (BFM), body fat percentage (BFP), and HOMA-IR (all p < 0.05). In contrast, preptin levels showed no significant correlation with BMI, BFM, or BFP, and demonstrated a non-significant positive association with HOMA-IR. CIMT was significantly higher in NASH patients (0.63 ± 0.09 mm vs. 0.49 ± 0.06 mm; p < 0.01), and positively correlated with BMI and LDL, but not with adropin, preptin, or HOMA-IR. Furthermore, both peptides exhibited moderate negative correlations with steatosis grade and necroinflammatory activity (p < 0.05), but they showed weak, non-significant negative correlations with fibrosis (p = 0.08). In multivariate analysis, only BMI was independently associated with NASH (OR = 1.44, 95% CI: 1.13–1.84, p = 0.004). Conclusion Reduced adropin and preptin levels in NASH patients were associated with metabolic and histological severity, independent of vascular changes. These peptides may serve as potential biomarkers for disease activity in NASH. But, further studies are needed to their clinical utility as biomarkers or therapeutic targets in NASH. Non-alcholic steatohepatitis adropin preptin CIMT8 Introduction Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which may progress to cirrhosis, liver failure, and hepatocellular carcinoma. Currently, NAFLD is the most common chronic liver disease worldwide, affecting 15–39% of the general population, with 3–6% progressing to NASH [ 1 ]. NASH is strongly associated with obesity, insulin resistance (IR), dyslipidemia, and type 2 diabetes mellitus (T2DM)—well-established risk factors for cardiovascular disease (CVD). Growing evidence suggests that cardiovascular complications, rather than liver-related outcomes, are the leading cause of mortality in patients with NAFLD, particularly those with NASH [ 2 ]. Carotid intima-media thickness (CIMT) is a non-invasive marker of early atherosclerotic changes and a reliable predictor of future CVDs. Multiple case–control and cross-sectional studies have reported increased CIMT among patients with NAFLD, and its severity correlates with the degree of hepatic steatosis and metabolic derangements. The possible biological mechanisms linking NAFLD and CVDs include systemic inflammation, increased oxidative stress, IR, and atherogenic dyslipidemia and endothelial dysfunctions. However, the relationship between NAFLD and atherosclerosis has been controversial and remains a crucial area of ongoing investigation [ 3 – 4 ]. Adropin and preptin are newly identified peptide hormones that play important roles in energy homeostasis and metabolic regulation. Emerging data suggest they may also mediate the interaction between metabolic dysfunction and vascular injury [ 5 ]. Adropin, encoded by the Enho gene, is primarily expressed in the liver, brain, and vascular endothelium. It enhances insulin sensitivity, promotes glucose oxidation, and suppresses fatty acid oxidation [ 6 , 7 ]. Decreased adropin levels have been reported in individuals with obesity, IR, and T2DM, implicating its role in NAFLD pathogenesis [ 8 , 9 ]. However, data on adropin levels in NASH patients remain limited. Beyond metabolic regulation, adropin has been shown to improve endothelial function and reduce vascular inflammation, with protective effects observed in angina, myocardial infarction, and coronary atherosclerosis [ 10 , 11 ]. Preptin is a pancreatic peptide co-secreted with insulin, derived from pro-IGF-II, and plays a key role in enhancing glucose-stimulated insulin secretion. Clinical and experimental studies suggest that preptin acts as a metabolic modulator, with elevated levels observed in conditions of such as obesity, T2DM, and polycystic ovary syndrome [ 12 ]. To date, no study has yet evaluated preptin levels in biopsy proven NASH patients. In contrast, reduced preptin levels have been linked to essential hypertension and impaired vascular health. Notably, lower circulating preptin levels have been associated with increased CIMT and the presence of carotid atherosclerotic plaques, indicating a potential role in endothelial dysfunction and atherosclerosis progression [ 6 , 13 ]. While adropin and preptin have individually been associated with metabolic and cardiovascular conditions, their combined role and association with CIMT in biopsy-confirmed NASH patients has not been previously explored. Therefore, this study aimed to assess serum adropin and preptin levels in patients with biopsy-proven NASH and healthy controls, and to investigate their association with metabolic parameters, liver histology, and carotid intima-media thickness. Material and Methods Patients This study was designed as a cross-sectional study (according to STROBE guidelines) and was conducted in the Gastroenterology Department, Kayseri Training and Research Hospital between January 2016 and July 2017. The study population comprised 40 biopsy proven NASH patients and 30 healthy controls. The study was approved by the Kayseri Training and Research Hospital Ethics Committee (No:09.2016.359) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants. Inclusion criteria for NASH patients were as follows; persistent liver enzyme elevation (> 1.5× for 6 months), ultrasonographic steatosis, and histologic features of NASH (steatosis > 5%, inflammation, Mallory bodies, fibrosis). Exclusion criteria included diabetes, hypertension, dyslipidemia, malignancy, systemic illness (e.g., cardiovascular, renal, or cerebrovascular disease), significant alcohol intake, cirrhosis, pregnancy/lactation, and smoking and refusing to sign the informed consent form. A control group (CG) of 30 age- and sex-matched healthy volunteers without liver disease, systemic illness, or alcohol/smoking history was enrolled. Blood samples were collected once from controls. Written informed consent was obtained from all participants. Anthropometric and biochemical measurements Anthropometric measurements were taken with participants lightly clothed and barefoot. BMI was calculated as weight/height² (kg/m²) and categorized as normal ( 30). Waist circumference > 80 cm in females and > 94 cm in males indicated abdominal obesity. BFM and BFP were measured via bioelectrical impedance (Tanita BC-148, Tokyo, Japan). Venous blood samples were collected after overnight fasting, centrifuged, and stored at − 80°C for adropin and preptin analysis. Total cholesterol (TC), triglycerides (TG), and high density lipoprotein (HDL) were measured enzymatically; LDL was calculated using the Friedewald formula. Glucose and insulin were assessed by standard methods, and IR was assessed by HOMA-IR: [glucose (mmol/L) × insulin (ng/mL)] / 22.5, with HOMA-IR > 2.7 indicating IR [ 14 ]. Serum adropin and preptin were measured using ELISA kits (Bioassay Technology, Shanghai), with detection limits of 5 ng/L and 10 ng/L, and intra- and inter-assay CVs < 8% and < 10%, respectively. Carotid intima media thickness measurements CIMT of all participants were measured by a single experienced radiologist using a Toshiba Aplio SSA-770A Doppler device with a 7.5 MHz linear transducer. After 8 hours of fasting and 10 minutes of rest, patients were scanned in the supine position with slight neck extension. Longitudinal USG images were obtained 1–2 cm proximal to the carotid bulb, and three manual measurements from the posterior wall were averaged. Statistical analysis Statistical analyses were performed using SPSS v15.0 (SPSS Inc., Chicago, IL, USA). Data normality was assessed by the Shapiro-Wilk test. Parametric data were expressed as mean ± SD, and non-parametric data as medians. Group comparisons were performed using Student’s t-test or Mann-Whitney U test, as appropriate. Categorical variables were compared using the χ² test. Pearson or Spearman correlation was applied based on data distribution. Logistic regression was used to identify factors independently associated with NASH. Odds ratios (OR) with 95% confidence intervals (CI) were reported, and p < 0.05 was considered statistically significant. Results Demographic and metabolic parameters of study population A total of 70 participants were enrolled: 40 patients with biopsy-proven NASH and 30 healthy controls. There were no significant differences in age and gender between two groups (p > 0.05). According to International Obesity Task Force criteria, 13.9% of NASH patients were overweight, and 86.1% were obese, while 40% of the CG were normal weight, 32.4 were overweight and 27.6% were obese. NASH patients exhibited significantly higher BMI, WC, BFM, and BFP compared to CG (all p < 0.001). The demographic, biochemical and ultrasonographic data of NASH patients and controls are shown in Table 1 . Table 1 The demographic, biochemical and ultrasonographic data of NASH patients and controls Variables NASH (n:40) Controls (n:30) p Age 40.8 ± 10.1 39.9 ± 7.6 NS Gender (M/F) 19/21 15/15 NS BMI, kg/m 2 35.6 ± 5.3 28.2 ± 3.7 < 0.001 WC (cm) 112.2 ± 10.1 91.7 ± 11.0 < 0.001 BFM (kg) 32.97 ± 9.96 24.6 ± 8.0 < 0.001 PBF (%) 35.8 ± 8.2 30.7 ± 7.67 < 0.001 HOMA-IR 4.1 (1.9–5.9) 1.9 (1.5–2.25) 0.001 AST (U/dl) 56 (36–87) 21 (16.5–25) 0.001 ALT (U/dl) 75 (46.2–114) 17 (13-25.5) 0.001 GGT (U/dl) 45.5 (28.7–60) 20 ( 14–30) 0.001 TC (mg/dL) 190.8 ± 14.4 183.3 ± 40.4 0.006 TG (mg/dL) 186.5 (122.2–210) 100 (82-162.7) 0.001 HDL (mg/dL) 44.5 ± 9.5 55.7 ± 9.9 < 0.001 LDL (mg/dL) 117.7 ± 17.3 98.9 ± 23.8 0.006 Adropin (ng/ml) 430.1 ± 197.5 590.7 ± 349.8 0.028 Preptin 1121.5 ± 421 1460.2 ± 775.3 0.035 CIMT mean 0.63 ± 0.09 0.49 ± 0.06 < 0.001 BMI: body mass index, WC: Waist circumference, BFM: body fat mass. PBF: percent of body fat, HOMA: Homeostasis model assessment-insulin resistance; AST: aspartate aminotransferase. ALT: alanine aminotransferase. GGT: gamma glutamyl transferase. TC: total cholesterol. TG: triglyceride. HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein cholesterol; CIMT: carotid intima media thickness. Serum AST, ALT, and GGT levels were significantly higher in the NASH group compared to controls (p < 0.05). Although TG, TC and LDL levels were within normal ranges, their means were significantly higher in NASH group (p < 0.05). HDL levels were significantly lower in NASH group (44.5 ± 9.5 vs. 55.7 ± 9.9; p < 0.05). HOMA-IR score was significantly higher in the NASH group than in CG [4.1 (1.9–5.9) vs. 1.9 (1.5–2.25); p < 0.05], with 72.5% of NASH patients having values above 2.5. Adropin, preptin levels and associated with metabolic parameters In the NASH group, mean serum adropin and preptin levels were lower than CG (adropin: 430.1 ± 197.5 vs. 590.7 ± 349.8, p = 0.02; preptin: 1121.5 ± 421 vs. 1460.2 ± 775.3, p = 0.35). Adropin was negatively correlated with BMI, BFM, and BFP (all p < 0.05), while preptin showed no such correlations. A strong positive correlation was found between adropin and preptin (r = 0.811, p < 0.001). Preptin was positively associated with glucose and HOMA-IR, but not significantly with HOMA-IR. Correlation of serum adropin and preptin levels with metabolic parameters and CIMT in NASH patients are shown in Table 2 . Table 2 Correlation between adropin, preptin, CIMT and biochemical variables Variable Adropin r p Preptin r p Age (years) -0.383 0.253 -0.218 0.215 BMI (kg/m 2 ) -0.241 NA -0.183 NA BFM (kg) − 0,383 0,02 0,245 0,231 BFP (%) − 0,349 0,03 − 0,370 0,034 Glucose (mg/dl) 0.189 NA 0.375 0.029 HOMA-IR 0.324 NA 0.443 0.07 TG (mg/dl) 0.247 NA 0.242 NA TC (mg/dl) 0.108 NA 0.129 NA LDL (mg/dl) 0.024 NA 0.013 NA HDL (mg/dl) 0.110 NA 0.099 NA Adropin (ng/ml) - - 0.811 < 0.001 Preptin (ng/ml) 0.811 < 0.001 - - CIMT (mm) 0.010 NA -0.013 NA BMI: Body mass index, CIMT: carotid intima-media thickness, CRP: C-reactive protein, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma glutamyl transferase, ALP: alkaline phosphatase, TG: Trygliseride, HDL: High-density lipoprotein, LDL: Low-density lipoprotein Univariate analysis showed BMI, glucose, ALT, LDL, HOMA-IR, and adropin were associated with NASH (all p 30 kg/m², n = 40) and non-obese (BMI < 30 kg/m², n = 30). Adropin and preptin levels were significantly lower in the obese group. Logistic regression analyses of factors associated with NASH are shown in Table 3 . Table 3 Logistic regression analyses of factors associated with NASH Risk factors OR 95% CI P Univariate analysis BMI 1.431 1.193–1.717 < 0.001 Glucose 1.110 1.032–1.195 0.005 ALT 1.141 1.055–1.234 0.001 LDL 1.026 1.006–1.047 0.012 Age 1.058 0.996–1.124 0.067 HOMA-IR 2.343 1.307-4.200 0.004 Adropin 0.998 0.996-1.000 0.039 Multiple analysis BMI 1.440 1.126–1.842 0.004 BMI: Body mass index. CRP: C-reactive protein. ALT: alanine aminotransferase. LDL: Low-density lipoprotein Adropin, preptin levels and associated with CIMT In NASH group, mean CIMT (average of right and left values) was also significantly higher than CG (0.63 ± 0.09 mm vs. 0.49 ± 0.06 mm, p < 0.01). Correlation analysis revealed that CIMT was positively correlated with BMI and LDL levels, and negatively correlated with HDL levels in the NASH group. However, no significant correlation was found between CIMT and serum adropin, preptin, HOMA-IR, TG and VLDL levels (all, p > 0.05). Correlation between serum adropin, preptin level and hepatic histopathology in NASH patients We also investigated the association between serum adropin and preptin levels and the severity of hepatic histology in NASH patients. Hepatic histolopathology was assessed using the Brunt scoring system. [3] Linear correlation analysis showed that serum adropin and preptin levels were significantly negatively correlated with steatosis grade (r = − 0.451, p = 0.002 and r = − 0.376, p = 0.008, respectively) and NAI (r = − 0.275, p = 0.04 and r = − 0.387, p = 0.03) and weak, non-significant correlation fibrosis (r=- 0.24, p = 0.08). Hepatic histopathology findings of NASH patients are shown in Table 4 . Discussion The aim of this study was to investigate the serum adropin and preptin levels and their association with CIMT among biopsy-proven NASH patients who did not have diabetes, hyperlipidemia, or hypertension. Our study is the first, to our knowledge, to evaluate circulating adropin and preptin levels together with CIMT in a biopsy-proven NASH cohort. The global prevalence of NAFLD is increasing with the obesity and diabetes epidemic. In Europe, Turkey has the highest rate (48.4%), followed by Italy (38.2%), while Germany, Portugal, and Spain report rates between 25–27% [ 15 ]. Obesity, IR, T2DM, and dyslipidemia are major risk factors for the progression to NASH, which affects up to 33.5% of obese and 37.5% of diabetic patients [ 16 ]. In present study, our findings align with these epidemiological trends. NASH patients were either obese (86.1%) or overweight (13.9%), and they exhibited significantly higher WC, BFM, and BFP compared to controls. CIMT is a reliable marker of early atherosclerosis and predicts CVD and stroke risk [ 2 – 5 ]. Many studies have shown NASH increases CVD risk, independent of traditional cardiometabolic factors. NAFLD may also contribute to increased CIMT through shared metabolic disturbances such as IR, central obesity, dyslipidemia, and low-grade inflammation [ 17 ]. However, the mechanisms linking NAFLD to CVD remain unclear. In a population-based study of 407 young Mexican Americans, Gill et al. reported a high NAFLD prevalence (48.8%) and noted 31.2% of those with NAFLD had subclinical atherosclerosis, highlighting the need for early screening < 45 years of age in this group [ 18 ]. In a meta-analysis by Teng et al., reported that NAFLD patients have a significantly greater mean CIMT than those without NAFLD (MD, 0.12; 95% CI, 0.08–0.17; p < 0.0001) [ 15 ]. In our study, the median CIMT of the NASH group was found to be significantly thicker than that of the CG [0.63 ± 0.09 mm vs. 0.49 ± 0.06 mm, p < 0.01], consistent previous studies. Preptin is a pancreatic hormone released alongside insulin, originating from IGF-2, and contributes to insulin secretion in response to glucose stimulation. Yang et al. reported significantly higher plasma preptin levels in T2DM patients compared to those with impaired glucose tolerance and controls (456 ± 14 vs. 416 ± 13 and 398 ± 13 ng/L, respectively), with strong positive correlations with BMI, insulin, and HOMA-IR [ 19 ]. It has been stated that elevated preptin levels in T2DM may result from increased secretion or reduced metabolism. Similarly, Kalaycı et al. also observed a positive association between preptin and HOMA-IR, suggesting its role in pathogenesis of IR and metabolic syndrome [ 20 ]. In addition, El-Eshmawy et al. found preptin positively correlated with BMI in obese individuals [ 21 ]. In contrast, our study found no significant correlation between serum preptin levels and BMI, BFM and BFP in the NASH group (p > 0.05) and a tendency toward positive correlation with HOMA-IR. However, participants with BMI > 30 kg/m² had significantly lower preptin levels, consistent with previous studies. These discrepancies within the NASH group may be due to differences in study design and population characteristics; as our cohort excluded patients with overt metabolic comorbidities. Despite its potential relevance in metabolic regulation, preptin has not been studied in patients with histologically confirmed NASH. There are only two studies conducted in NAFLD patients diagnosed by USG in the literatüre. Argun et al. compared serum preptin levels in NAFLD patients by confirmed USG and 35 controls, excluding those with IR or diabetes. They found that the NAFLD group had significantly higher preptin levels compared to controls (83.7 ± 71.1 pg/mL vs. 56.5 ± 8.1 pg/mL; p < 0.001). Furthermore, in linear regression analysis, the FIB-4 score was an independent predictor of preptin levels (p < 0.05), with each 1-unit increase in FIB-4 score associated with an 86.37-units decrease in serum preptin levels (R² = 8.5%) [ 22 ]. In another study, Wang Jinjun et al. found that serum preptin levels were significantly higher in NAFLD patients compared to controls (p < 0.001), and were positively correlated with BMI and HOMA-IR (p < 0.001) [ 23 ]. In contrast, our study demonstrated significantly lower preptin levels in the NASH group despite higher rates of obesity and IR, consistent with the findings of Argun et al. Furthermore, preptin levels showed a moderate negative correlation with both steatosis grade (r = − 0.376, p = 0.008) and NAI (r = − 0.387, p = 0.030), indicating a potential link between preptin and histological severity in NASH. The reduction in preptin levels observed in NASH may be attributed to β-cell dysfunction induced by chronic metabolic stress, as well as impaired hepatic processing and clearance of preptin secondary to progressive hepatic fibrosis [ 22 ]. These findings support the possibility that preptin secretion and regulation follows a biphasic pattern during the NAFLD progression. Preptin is also involved in the pathogenesis in CVDs and demonstrated that the preptin single gene polymorphism (rs1003483 and rs1004446 only) were associated with increased susceptibility to CADs and hypertension [ 24 ]. Cia et al found that hypertensive patients had significantly lower plasma preptin levels (1930.30 ± 268.47 vs. 2182.88 ± 325.81 pg/mL, P < 0.01), which were negatively correlated with CIMT (r = -0.47, P < 0.01) and independently related to SBP and TC levels [ 13 ]. In contrast, Li et al showed that circulating preptin is increased in patients with positive coronary calcification, which is a specific feature of coronary CAD [ 25 ]. Yassen et al. reported that CAD cases both with and without T2DM had a significantly higher serum preptin than the CG [ 26 ]. In our NASH cohort, we did not find a statistically significant correlation between preptin levels and CIMT. These contradictory results may be attributed to small sample size, differences of study population and variations in preptin allele frequencies across different ethnic groups. Adropin is a novel peptide hormone that plays a key role in regulating energy balance, as well as glucose and lipid homeostasis. Prior studies have shown that adropin improves insulin resistance, enhances glucose uptake and tolerance, and supports metabolic control—all of which are essential mechanisms in diseases such as obesity, IR and T2DM. Epidemiological studies also suggest that serum adropin levels are significantly reduced in NAFLD patients [ 6 – 7 ]. Recently, Chen et al. conducted the first study involving biopsy-proven NASH patients and demonstrated significantly lower adropin levels in NASH (9.99 ± 5.51 ng/ml) compared to ultrasound-normal, histologically normal, and NAFLD groups. Additionally, serum adropin showed negative associations with insulin, HOMA-IR, and LDL levels [ 9 ]. In our study, serum adropin levels were also significantly lower in the NASH group (p = 0.02). Adropin levels showed no correlation with HOMA-IR and lipid parameters, due to exclusion of patients with overt metabolic syndrome. Recent studies have shown that adropin is closely linked to cardiovascular diseases, including coronary artery disease, hypertension and heart failure. Reduced adropin may contribute to both metabolic dysregulation and endothelial dysfunction, thereby promoting atherosclerosis. Experimental studies have shown that synthetic adropin enhances lipoprotein lipase expression, improves lipid clearance, and increases endothelial nitric oxide production, supporting vascular integrity and reducing inflammation [ 6 , 27 ]. Clinically, Zhao et al. reported significantly lower serum adropin levels in patients with CVD, which were associated with more severe coronary atherosclerosis [ 28 ]. Similarly, Wei et al. found that higher adropin levels were independently associated with lower CIMT in T2DM patients [ 29 ]. Similarly, Wu et al showed that T2DM patients had significantly lower serum adropin levels [(5.53 ± 1.62) ng/mL vs. (4.80 ± 1.48) ng/mL, p < 0.001] and higher angiographic atherosclerosis scores than non-diabetic individuals [ 30 ]. In line with these findings, our study also showed significantly reduced serum adropin levels in NASH patients. However, unlike previous reports, we did not observe a significant correlation between adropin and CIMT values. This discrepancy may be attributed to differences in study populations (e.g., exclusion of patients with diabetes or dyslipidemia), sample size limitations, or disease-specific mechanisms unrelated to traditional atherosclerotic pathways. This study has some limitations. First, its cross-sectional design precludes causal inference. Second, the relatively small sample size may have limited the statistical power to detect modest associations, particularly with CIMT. Third, lack of a simple steatosis group in the study population prevented direct comparison with NASH patients. This is the first clinical study to explore the relationship between serum adropin and preptin levels and CIMT in biopsy-proven NASH patients. In NASH patients, both peptides were significantly reduced and negatively associated with severity of steatosis and NAI, while no association was observed with CIMT. Notably, our findings suggest that preptin may exhibit a biphasic secretion pattern during the progression of NAFLD. These results imply that adropin and preptin may serve as potential biomarkers for disease activity in NASH, independent of vascular changes. Nevertheless, further large-scale studies are warranted to clarify their clinical utility as biomarkers or therapeutic potential. Declarations Author contributions : Ozel Coskun BD. wrote the main manuscript text and D.O and C.I done the literature review and data analysis, K.A done tables. All authors reviewed the manuscript Funding No funding was received for the conduct of this study. Data availability No applicable Ethics approval and consent to participate This study was approved by the Ethics Committee of KayseriTraining and Research Hospital (Approval no:09.2016.359). Written informed consent was obtained from all patients included in the study in accordance with the ethical standards and the Declaration of Helsinki. 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Wang H, Wang X, Cao Y, Han W, Guo Y, Yang G, et al. Association of polymorphisms of preptin, irisin and adropin genes with susceptibility to coronary artery disease and hypertension. Medicine (Baltimore) 2020; 99 (10): e19365. 27 Li B, Li Y, Zhang T, Song L, Lei C, Zhao Y, et al. Preptin is a new predictor of coronary artery calcification. Clin Chim Acta 2018; 485:133-138. Yassen ST, Farhan LO. Evaluation of Preptin and other Biomarkers in Coronary Artery Disease Patients with and without Diabetes Mellitus. J Fac Med Baghdad 2024; 66(4):431–436. Altamimi TR, Gao S, Karwi QG, Fukushima A, Rawat S, Wagg CS, et al. Adropin regulates cardiac energy metabolism and improves cardiac function and efficiency. Metabolism 2019; 98: 37-48. Zhao L‑P, You T, Chan S‑P, Chen J‑C, Xu W‑T. Adropin is associated with hyperhomocysteine and coronary atherosclerosis. Exp Ther Med. 2016;11(3): 1065–1070. Wei W, Liu H, Qiu X, Zhang J, Huang J, Chen H, et al. The association between serum adropin and carotid atherosclerosis in patients with type 2 diabetes mellitus: a cross‑sectional study. Diabetol Metab Syndr 2022; 14(1): 27. Wu L, Fang J, Chen L, Zhao Z, Luo Y, Lin C, et al. Low serum adropin is associated with coronary atherosclerosis in type 2 diabetic and non-diabetic patients. Clin Chem Lab Med. 2014; 52 (5): 751-8. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 18 Nov, 2025 Reviews received at journal 01 Oct, 2025 Reviewers agreed at journal 22 Sep, 2025 Reviews received at journal 07 Sep, 2025 Reviewers agreed at journal 04 Sep, 2025 Reviewers agreed at journal 04 Sep, 2025 Reviewers invited by journal 02 Sep, 2025 Editor assigned by journal 06 Aug, 2025 Submission checks completed at journal 04 Aug, 2025 First submitted to journal 02 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7279629","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":511368936,"identity":"9b67a116-6630-40e2-8b09-9b200affc6dd","order_by":0,"name":"Banu Demet Coskun","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYDCCA1BagoGB8cEHIIONnRgtByBamA1ngLQwk6CFTZoHJEJIC9/x7sTHH2ps7CVn5B6Qtvm1TZ6PmYHxw8cc3Fokz5zdbHDgWFribIm8BOPcvtuGbcwMzJIzt+HWYnAjd5vEwYbDCXISOQbJuT23GYFa2Jh58Wm5/3b7D6AWe5CWw5Y9t+0Ja7kBlAVqYZwtkWPYzPDjdiJBLZJncjdLnAH6ZWbPG2PG3obbyW3MjM14/cJ3/OzGDxXAEJM4nmP+48ef27bz25sPfviIRwsqYGwDkw3EqgeBP6QoHgWjYBSMgpECAIUJVgzNhxXcAAAAAElFTkSuQmCC","orcid":"","institution":"Health Science University","correspondingAuthor":true,"prefix":"","firstName":"Banu","middleName":"Demet","lastName":"Coskun","suffix":""},{"id":511368937,"identity":"217c0c2a-4bc0-446a-baef-20977a991d50","order_by":1,"name":"Oguzhan Dizdar","email":"","orcid":"","institution":"Kayseri Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Oguzhan","middleName":"","lastName":"Dizdar","suffix":""},{"id":511368938,"identity":"a14197c8-c524-4b3f-a239-dca49c43b94e","order_by":2,"name":"Isıl Cakır","email":"","orcid":"","institution":"Kayseri Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Isıl","middleName":"","lastName":"Cakır","suffix":""},{"id":511368939,"identity":"0d44baa3-9492-42e4-800d-cf381876a1e0","order_by":3,"name":"Ali Koc","email":"","orcid":"","institution":"Kayseri Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ali","middleName":"","lastName":"Koc","suffix":""}],"badges":[],"createdAt":"2025-08-02 17:08:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7279629/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7279629/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90823221,"identity":"77d68342-3cd8-4eeb-bb49-026b642e6dcb","added_by":"auto","created_at":"2025-09-08 14:50:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":859801,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7279629/v1/e0ae5152-e28f-4c4b-ae0d-3756d970f2f0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Circulating Adropin and Preptin In Non-Alcoholic Steatohepatitis and Their Relationship with Carotid Intima Media Thickness","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNon-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which may progress to cirrhosis, liver failure, and hepatocellular carcinoma. Currently, NAFLD is the most common chronic liver disease worldwide, affecting 15\u0026ndash;39% of the general population, with 3\u0026ndash;6% progressing to NASH [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. NASH is strongly associated with obesity, insulin resistance (IR), dyslipidemia, and type 2 diabetes mellitus (T2DM)\u0026mdash;well-established risk factors for cardiovascular disease (CVD). Growing evidence suggests that cardiovascular complications, rather than liver-related outcomes, are the leading cause of mortality in patients with NAFLD, particularly those with NASH [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCarotid intima-media thickness (CIMT) is a non-invasive marker of early atherosclerotic changes and a reliable predictor of future CVDs. Multiple case\u0026ndash;control and cross-sectional studies have reported increased CIMT among patients with NAFLD, and its severity correlates with the degree of hepatic steatosis and metabolic derangements. The possible biological mechanisms linking NAFLD and CVDs include systemic inflammation, increased oxidative stress, IR, and atherogenic dyslipidemia and endothelial dysfunctions. However, the relationship between NAFLD and atherosclerosis has been controversial and remains a crucial area of ongoing investigation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAdropin and preptin are newly identified peptide hormones that play important roles in energy homeostasis and metabolic regulation. Emerging data suggest they may also mediate the interaction between metabolic dysfunction and vascular injury [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Adropin, encoded by the Enho gene, is primarily expressed in the liver, brain, and vascular endothelium. It enhances insulin sensitivity, promotes glucose oxidation, and suppresses fatty acid oxidation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Decreased adropin levels have been reported in individuals with obesity, IR, and T2DM, implicating its role in NAFLD pathogenesis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, data on adropin levels in NASH patients remain limited. Beyond metabolic regulation, adropin has been shown to improve endothelial function and reduce vascular inflammation, with protective effects observed in angina, myocardial infarction, and coronary atherosclerosis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePreptin is a pancreatic peptide co-secreted with insulin, derived from pro-IGF-II, and plays a key role in enhancing glucose-stimulated insulin secretion. Clinical and experimental studies suggest that preptin acts as a metabolic modulator, with elevated levels observed in conditions of such as obesity, T2DM, and polycystic ovary syndrome [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. To date, no study has yet evaluated preptin levels in biopsy proven NASH patients. In contrast, reduced preptin levels have been linked to essential hypertension and impaired vascular health. Notably, lower circulating preptin levels have been associated with increased CIMT and the presence of carotid atherosclerotic plaques, indicating a potential role in endothelial dysfunction and atherosclerosis progression [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWhile adropin and preptin have individually been associated with metabolic and cardiovascular conditions, their combined role and association with CIMT in biopsy-confirmed NASH patients has not been previously explored. Therefore, this study aimed to assess serum adropin and preptin levels in patients with biopsy-proven NASH and healthy controls, and to investigate their association with metabolic parameters, liver histology, and carotid intima-media thickness.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003e\u003cb\u003ePatients\u003c/b\u003e\u003c/p\u003e\u003cp\u003e This study was designed as a cross-sectional study (according to STROBE guidelines) and was conducted in the Gastroenterology Department, Kayseri Training and Research Hospital between January 2016 and July 2017. The study population comprised 40 biopsy proven NASH patients and 30 healthy controls. The study was approved by the Kayseri Training and Research Hospital Ethics Committee (No:09.2016.359) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants.\u003c/p\u003e\u003cp\u003eInclusion criteria for NASH patients were as follows; persistent liver enzyme elevation (\u0026gt;\u0026thinsp;1.5\u0026times; for 6 months), ultrasonographic steatosis, and histologic features of NASH (steatosis\u0026thinsp;\u0026gt;\u0026thinsp;5%, inflammation, Mallory bodies, fibrosis). Exclusion criteria included diabetes, hypertension, dyslipidemia, malignancy, systemic illness (e.g., cardiovascular, renal, or cerebrovascular disease), significant alcohol intake, cirrhosis, pregnancy/lactation, and smoking and refusing to sign the informed consent form. A control group (CG) of 30 age- and sex-matched healthy volunteers without liver disease, systemic illness, or alcohol/smoking history was enrolled. Blood samples were collected once from controls. Written informed consent was obtained from all participants.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAnthropometric and biochemical measurements\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAnthropometric measurements were taken with participants lightly clothed and barefoot. BMI was calculated as weight/height\u0026sup2; (kg/m\u0026sup2;) and categorized as normal (\u0026lt;\u0026thinsp;25), overweight (25\u0026ndash;29), or obese (\u0026gt;\u0026thinsp;30). Waist circumference\u0026thinsp;\u0026gt;\u0026thinsp;80 cm in females and \u0026gt;\u0026thinsp;94 cm in males indicated abdominal obesity. BFM and BFP were measured via bioelectrical impedance (Tanita BC-148, Tokyo, Japan). Venous blood samples were collected after overnight fasting, centrifuged, and stored at \u0026minus;\u0026thinsp;80\u0026deg;C for adropin and preptin analysis. Total cholesterol (TC), triglycerides (TG), and high density lipoprotein (HDL) were measured enzymatically; LDL was calculated using the Friedewald formula. Glucose and insulin were assessed by standard methods, and IR was assessed by HOMA-IR: [glucose (mmol/L) \u0026times; insulin (ng/mL)] / 22.5, with HOMA-IR\u0026thinsp;\u0026gt;\u0026thinsp;2.7 indicating IR [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Serum adropin and preptin were measured using ELISA kits (Bioassay Technology, Shanghai), with detection limits of 5 ng/L and 10 ng/L, and intra- and inter-assay CVs\u0026thinsp;\u0026lt;\u0026thinsp;8% and \u0026lt;\u0026thinsp;10%, respectively.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCarotid intima media thickness measurements\u003c/b\u003e\u003c/p\u003e\u003cp\u003eCIMT of all participants were measured by a single experienced radiologist using a Toshiba Aplio SSA-770A Doppler device with a 7.5 MHz linear transducer. After 8 hours of fasting and 10 minutes of rest, patients were scanned in the supine position with slight neck extension. Longitudinal USG images were obtained 1\u0026ndash;2 cm proximal to the carotid bulb, and three manual measurements from the posterior wall were averaged.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eStatistical analyses were performed using SPSS v15.0 (SPSS Inc., Chicago, IL, USA). Data normality was assessed by the Shapiro-Wilk test. Parametric data were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, and non-parametric data as medians. Group comparisons were performed using Student\u0026rsquo;s t-test or Mann-Whitney U test, as appropriate. Categorical variables were compared using the χ\u0026sup2; test. Pearson or Spearman correlation was applied based on data distribution. Logistic regression was used to identify factors independently associated with NASH. Odds ratios (OR) with 95% confidence intervals (CI) were reported, and p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eDemographic and metabolic parameters of study population\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA total of 70 participants were enrolled: 40 patients with biopsy-proven NASH and 30 healthy controls. There were no significant differences in age and gender between two groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). According to International Obesity Task Force criteria, 13.9% of NASH patients were overweight, and 86.1% were obese, while 40% of the CG were normal weight, 32.4 were overweight and 27.6% were obese. NASH patients exhibited significantly higher BMI, WC, BFM, and BFP compared to CG (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The demographic, biochemical and ultrasonographic data of NASH patients and controls are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe demographic, biochemical and ultrasonographic data of NASH patients and controls\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNASH\u003c/p\u003e\u003cp\u003e(n:40)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eControls\u003c/p\u003e\u003cp\u003e(n:30)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40.8\u0026thinsp;\u0026plusmn;\u0026thinsp;10.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e39.9\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGender (M/F)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19/21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15/15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI, kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eWC (cm)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e112.2\u0026thinsp;\u0026plusmn;\u0026thinsp;10.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e91.7\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBFM (kg)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32.97\u0026thinsp;\u0026plusmn;\u0026thinsp;9.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24.6\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePBF (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30.7\u0026thinsp;\u0026plusmn;\u0026thinsp;7.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHOMA-IR\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.1\u0026nbsp; (1.9\u0026ndash;5.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.9 (1.5\u0026ndash;2.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAST\u0026nbsp; (U/dl)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e56 (36\u0026ndash;87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21 (16.5\u0026ndash;25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eALT\u0026nbsp; (U/dl)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e75 (46.2\u0026ndash;114)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17 (13-25.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGGT\u0026nbsp; (U/dl)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45.5 (28.7\u0026ndash;60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 ( 14\u0026ndash;30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTC (mg/dL)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e190.8\u0026thinsp;\u0026plusmn;\u0026thinsp;14.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e183.3\u0026thinsp;\u0026plusmn;\u0026thinsp;40.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.006\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTG (mg/dL)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e186.5 (122.2\u0026ndash;210)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100 (82-162.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHDL (mg/dL)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e55.7\u0026thinsp;\u0026plusmn;\u0026thinsp;9.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLDL (mg/dL)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e117.7\u0026thinsp;\u0026plusmn;\u0026thinsp;17.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e98.9\u0026thinsp;\u0026plusmn;\u0026thinsp;23.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.006\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAdropin (ng/ml)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e430.1\u0026thinsp;\u0026plusmn;\u0026thinsp;197.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e590.7\u0026thinsp;\u0026plusmn;\u0026thinsp;349.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.028\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePreptin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1121.5\u0026thinsp;\u0026plusmn;\u0026thinsp;421\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1460.2\u0026thinsp;\u0026plusmn;\u0026thinsp;775.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.035\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCIMT mean\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eBMI: body mass index, WC: Waist circumference, BFM: body fat mass. PBF: percent of body fat, HOMA: Homeostasis model assessment-insulin resistance; AST: aspartate aminotransferase. ALT: alanine aminotransferase. GGT: gamma glutamyl transferase. TC: total cholesterol. TG: triglyceride. HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein cholesterol; CIMT: carotid intima media thickness.\u003c/p\u003e\u003cp\u003eSerum AST, ALT, and GGT levels were significantly higher in the NASH group compared to controls (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Although TG, TC and LDL levels were within normal ranges, their means were significantly higher in NASH group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). HDL levels were significantly lower in NASH group (44.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5 vs. 55.7\u0026thinsp;\u0026plusmn;\u0026thinsp;9.9; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). HOMA-IR score was significantly higher in the NASH group than in CG [4.1 (1.9\u0026ndash;5.9) vs. 1.9 (1.5\u0026ndash;2.25); p\u0026thinsp;\u0026lt;\u0026thinsp;0.05], with 72.5% of NASH patients having values above 2.5.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAdropin, preptin levels and associated with metabolic parameters\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn the NASH group, mean serum adropin and preptin levels were lower than CG (adropin: 430.1\u0026thinsp;\u0026plusmn;\u0026thinsp;197.5 vs. 590.7\u0026thinsp;\u0026plusmn;\u0026thinsp;349.8, p\u0026thinsp;=\u0026thinsp;0.02; preptin: 1121.5\u0026thinsp;\u0026plusmn;\u0026thinsp;421 vs. 1460.2\u0026thinsp;\u0026plusmn;\u0026thinsp;775.3, p\u0026thinsp;=\u0026thinsp;0.35). Adropin was negatively correlated with BMI, BFM, and BFP (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), while preptin showed no such correlations. A strong positive correlation was found between adropin and preptin (r\u0026thinsp;=\u0026thinsp;0.811, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Preptin was positively associated with glucose and HOMA-IR, but not significantly with HOMA-IR. Correlation of serum adropin and preptin levels with metabolic parameters and CIMT in NASH patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCorrelation between adropin, preptin, CIMT and biochemical variables\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAdropin\u003c/p\u003e\u003cp\u003er\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePreptin\u003c/p\u003e\u003cp\u003er\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.383\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.253\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.218\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.215\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI (kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.241\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eNA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.183\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBFM\u0026nbsp; (kg)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026minus;\u0026thinsp;0,383\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e0,02\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0,245\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0,231\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBFP (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026minus;\u0026thinsp;0,349\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e0,03\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026minus;\u0026thinsp;0,370\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0,034\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGlucose (mg/dl)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.189\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.375\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.029\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHOMA-IR\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.324\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eNA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.443\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.07\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTG (mg/dl)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.247\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.242\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTC (mg/dl)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.108\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.129\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLDL (mg/dl)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHDL (mg/dl)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.110\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.099\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAdropin (ng/ml)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.811\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePreptin (ng/ml)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.811\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCIMT (mm)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eBMI: Body mass index, CIMT: carotid intima-media thickness, CRP: C-reactive protein, AST: aspartate aminotransferase, ALT: alanine aminotransferase, GGT: gamma glutamyl transferase, ALP: alkaline phosphatase, TG: Trygliseride, HDL: High-density lipoprotein, LDL: Low-density lipoprotein\u003c/p\u003e\u003cp\u003eUnivariate analysis showed BMI, glucose, ALT, LDL, HOMA-IR, and adropin were associated with NASH (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), but only BMI remained an independent predictor in multivariate analysis (OR: 1.440, 95% CI: 1.126\u0026ndash;1.842, p\u0026thinsp;=\u0026thinsp;0.004). Patients were divided into two groups based on BMI: obese (BMI\u0026thinsp;\u0026gt;\u0026thinsp;30 kg/m\u0026sup2;, n\u0026thinsp;=\u0026thinsp;40) and non-obese (BMI\u0026thinsp;\u0026lt;\u0026thinsp;30 kg/m\u0026sup2;, n\u0026thinsp;=\u0026thinsp;30). Adropin and preptin levels were significantly lower in the obese group. Logistic regression analyses of factors associated with NASH are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eLogistic regression analyses of factors associated with NASH\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRisk factors\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnivariate analysis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.431\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.193\u0026ndash;1.717\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGlucose\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.110\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.032\u0026ndash;1.195\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eALT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.141\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.055\u0026ndash;1.234\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLDL\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.026\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.006\u0026ndash;1.047\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.012\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.058\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.996\u0026ndash;1.124\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.067\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHOMA-IR\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2.343\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.307-4.200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAdropin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.998\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.996-1.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.039\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMultiple analysis\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.440\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.126\u0026ndash;1.842\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eBMI: Body mass index. CRP: C-reactive protein. ALT: alanine aminotransferase. LDL: Low-density lipoprotein\u003c/p\u003e\u003cp\u003e\u003cb\u003eAdropin, preptin levels and associated with CIMT\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn NASH group, mean CIMT (average of right and left values) was also significantly higher than CG (0.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09 mm vs. 0.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06 mm, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Correlation analysis revealed that CIMT was positively correlated with BMI and LDL levels, and negatively correlated with HDL levels in the NASH group. However, no significant correlation was found between CIMT and serum adropin, preptin, HOMA-IR, TG and VLDL levels (all, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003e\u003cb\u003eCorrelation between serum adropin, preptin level and hepatic histopathology in NASH patients\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe also investigated the association between serum adropin and preptin levels and the severity of hepatic histology in NASH patients. Hepatic histolopathology was assessed using the Brunt scoring system.\u003csup\u003e[3]\u003c/sup\u003e Linear correlation analysis showed that serum adropin and preptin levels were significantly negatively correlated with steatosis grade (r = \u0026minus;\u0026thinsp;0.451, p\u0026thinsp;=\u0026thinsp;0.002 and r = \u0026minus;\u0026thinsp;0.376, p\u0026thinsp;=\u0026thinsp;0.008, respectively) and NAI (r = \u0026minus;\u0026thinsp;0.275, p\u0026thinsp;=\u0026thinsp;0.04 and r = \u0026minus;\u0026thinsp;0.387, p\u0026thinsp;=\u0026thinsp;0.03) and weak, non-significant correlation fibrosis (r=- 0.24, p\u0026thinsp;=\u0026thinsp;0.08). Hepatic histopathology findings of NASH patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cimg 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J8OGVhbGDIcVxgpgQtnW1lZqqeAYU5+nd7Do9WMApTHvr8T8bGFlYcxweEjKDIJlxIwVy/YM9zCMMcZUYYVhjDGmCisMY4wxVVhhGGOMqcIKwxhjTBVWGMYYY6qwwjDGGFOFFYYxxpgqqifuGWPMpuKJe4d4prcZBMuIGSuW7RkekjLGGFOFFYYxxpgqrDCMMcZUYYVhjDGmCisMY4wxVVhhGGOMqcIKwxhjTBVWGMYYY6oYRGGwOD+TW3Dfv3+fPHz4cHrmdGDxf/LCthbuAQfkn+vz+1C8guO//vpremSMMeNmYYVBpfnkyZM0ExJ369atpDQE+2/fvp0ezY8q8WVCGp8+fZo8fvw43c/Lly8n+/v7aRuVzv379ycHBwfTo8nk2rVrk5s3b1ppGGM2goUVxq9fv6Z7h3z79m26dwgK5KSoIp8XKnKUF9s+pPBevHiRjr98+ZK2ulbH5OXBgweTS5cupWOBkuGeF1GKxhizDiysMK5cuZK2cQjn/fv3aUvLmxb53bt3j3oK+BE2tsrlh1M4KmAq8g8fPkwuX76c/DiXh6MHIz+F0zHKoO185M2bN5Otra0/FEGEOF69ejW5evXqUVwRlOLTp0+nR8YYM04WVhhUtAzfAEM4VKZqbasS3tvbSy1xFAqtcVr/apVTqaMUiGN7ezspCTh//nza4kdY9QQIh2Mfv3fv3k12dnZSnFIIu7u7aQtt5yMog+iPUgDiBo7J9+vXr9OQFHGTp/h94+LFi8eGqowxZowM8tFbQ0CqqOlRwI0bN9JWfPz4MVWsKBW2nz9/Prr22bNnSXGIfDhJQ0Pnzp1LDvC7fft2UlT0UtSzifSdz4fQSBcFc/369bRlyA3FR5rk+cKFC+mYe8lB+RhjzFhZWGHQS1CPgl6EehulypPhHxQETt8NaOHTeqflPi9U3sQF+VAR9J1v63WQL+UP5ad89qEelTHGjJFBehhUqlIQ+gjeVnky1k8rXd8W+A6BssGPIai8tR/RUNHv37+TA/wUB70HlJGGkkTfefJZSpdhJ4bTgHBc//Pnz5T3+DH/x48f6ZwxxoyapiXdS1ewpkJNrqkwUzhcowDSObbyIwzomPDQ9EiO/HZ2dtJ2d3c3nWt6HOmYLeCvsArDNg+nMKTRdj6iPCrPgvzm4WNeI6Sj+9tU8mdizFiwbM/winsN9EL4fbftG0cfi1w7JsYuI2ZzsWzPsMKYQsUPfIepheEtPtZvurIAv1RmrFi2Z1hhmEGwjJixYtmeMchHb2OMMePHCsMYY0wVVhjGGGOqsMIwxhhTxWAKgxnTfBzCleBPJIWJM8FL/mZcMBEy2uAClXtf+eMfDVYCcqO/2yAasewil1Xi1nE+sZP8Kk/Eb/k0m8wgCoOZ1NhW4k+C0t8EetE4v7u7O3n+/Hk6LvmbcUHFi02vCHIjmcFhu6sNKnFm1ue/L8tQJaA4sBiseHLlItpkFZnb29tLZm34TVqQLvbQZLWA9MlHrlSM2RQGURi8qJjG6HuRNMcBkx5YeBUlfzMesMdFgyBy586d6d6MNpMy2BnLzbeggGJ8yJAMVj569OiYIctIrawCpu/zPJIP8mPMJjKIwpAVWiy80oJrI1YEvIhSEiV/s1nQ02xrLKh3EVHLv4TsfrXRJqsoGOyh4ad1TVBI+LfhXobZVAZRGLygOF7EroWEqBQYJ2ZoIo49l/zN5sC6JTIwGcGEfa5I2lr+ESpzVkdso01WOdYQFb0UKST82yA/MrdvzCYx2Edv4AVrMxcu9GIylMAKdqLkbzYHLP7ma6AA/hF6BaWWv6jpqXbJqhQSikMfw/WtTeT5MmYTGFRhgFpldOn1suW9htLL7OEok5P3Llj5kOEm5IqP3jhkTSBr9+7dmx51I1mNcL0UEh/A+RiOy3/G8Lc2s4kMqjBo/WlsWYsQ4XJFQMstH5eGkr8ZN1Fuchimiq15/lSSXNEjxWmBK32ToKdCj6BreLMtTeQPoiLRUsER8tM2fGbM6GlevF66grEOBOdxrGdRonmxj8LFdSZK/ma9oPy6iOWcy0mX3ADrjeTrlQBx4oA4FL8c1+DYZy2TLlklXNf6JzF98mM2B8rfHGJrtWYQlikjtPzbfq09DfjuwbBY2/cWM05c/80Y/BuGMUND5czvsKXJeKuC9MmHlYXZVNzDMINgGTFjxbI9wz0MY4wxVVhhGGOMqcIKwxhjTBVWGMYYY6oYRGEwQYoPQ7hoQqHkX0LrGWgClij5m/WCGdlxVraoWUsF+dFfUiW5kl/buYjXwzDmZCysMPQC8RfB7u7J17ngZZVNqWhYruRv1gsq3nw9DKARkK9PkSMLAMzyLskV8SgO3E5hbY229LwehjF1DNLDkOmPk65zQcuNl18mHkTJ36wfbethQM36FPmkvTa5amtMtNmK8noYxixA08rqpTJY0cRDl+kHTC5gagGzDKSjsCV/czapkZFGYbSa5MBxPaY7cjDPMa9cER9ptdGWno5xpAfEjX8bnFM4M35qZHtTGKSHwTABQ0cnWefi69evaUyZll+TnxSW1l/J34wLegG4pnI+Wp8i0rYeRp9cldbWgLb0OEbGcMziRs68HoYxfzKIwtALx5DDvOtc/Pz5c3Lz5s0jcwtN6y29jCV/M06QFRoIOW3rTvTJFdf0me8opQdeD8OYdgZRGKK0nkX05+OnXkJahxcuXDj28tF6w6/kb8YLlXhO3ruIlOStlrb0kEmvh2FMO4MqDFpkfetc5Otk0JJjaEEtOFqMV65cKfqbccLfS21rYjC0VGrNt8lbKZ6ctnDEB1GReD0MYwJNxd1LVzA+LnIed9J1LuK6A/HDZ8nfnD0ooy6iPOhjNWWa+7XBzw/6AN0nV3k8+qCNLHWlR7g8vih/Sh/Ij9kcKH9ziK3VmkFYpozQ8vd6GOa0cP03Y9AhKWOWAZWz18Mw5vRxD8MMgmXEjBXL9gz3MIwxxlRhhWGMMaYKKwxjjDFVWGEYY4ypYuUKQ3aAcJGSvxkfTJpTWbNfA/Khv6TYtslKlCFN+IzE85qkJ7zuhTEV8JdUH5XBetHEqdzSZ8nfrA/zyAhhmQinSXV9IBeaLMfEPckJk+/iZDtN8MO1Ta4jPLLG9fE6jvGPcL3l0cA8sj12VqYwVDmwjZT8zXpRKyN5Za5Kvou2yh8kO5ArAZRDXuGXFEY+61uU0jWbxRD131hYeEiK7n3bsps5mJxuXsy0eE0cEij5m3EiO00Y+WPYB1tQbUYABfLQZp8MuA65ASwZY91YtJkgx6jg3bt3J9evXz8ybY7sythgDulaHo2ZsbDCaJROMuKmseHSbNxPnz6lLeGbVt7RqmUlfzNemC395MmTVCH3raZIpV+yDEtl/uDBg+lRPygY5AzHbG2u97oXxtQzyEdvLMvqRaTlhuLIP2ZiB0gtOcIfHBykFmbJ34wXFsfa399PZd3XO+1ad4J1KxYxce51L4yZj8H+kuJF44VjDQEUBy9iBKNtv3//nh5N0lACLbuSvxknyImM9yEn9Da6hn1KvQuGtO7duzc9OjSDrt4qsN9lgtzrXhgzP4N8w8AxvEAF8P79++mZ4zDUxIsJVBBa7azkb8YJjYMPHz5Mj/ppWw9DvVeUDgqIyp99eqsc49gvGQmUgooNE697YUwFTSXfS2WwXvgbhbjy+Er+Zn2Yp+za1sbooul1Hv1JFWVFTuf4+yn3y8Hf616YeUAuzCG2VmsGYZkyQo9g1etheN0LI1z/zRhsSCp3tTN4jemDSnuV62GQjte9MOZP3MMwg2AZMWPFsj1jsL+kjDHGjBsrDGOMMVVYYRhjjKliYYXBTF196I5u0fkU/FtPPF2Tusx6QxnjhCZ/4tivgXClj+HIZj6TvJRGm7/NnBtznEF6GAcHB+mjELO0td+nMFAEXX9SYfJhe3t7emTGCPakIkz+RH5wJYODEWSIcG2TRVEUL1++nB7NKKXR5k+87LvRYswhCysMjMe1mfIozfgWmt1tNhMq9N3d3enRbJY/soSrqai75mYglzF+KKXRlTbx2yCmMYes5BuGuvrqdVBZYB4CU9Ps83IqzKr+tTenB+WNldhIjXnyCHGoJ1BLKY2+tN3LMOaQpSsMlATdfIapePFQCLT+GG7C2Bv79DawXkoY2QMy40VWYheBCn1VhgH7lJcxm8JSFYYqfrr5gHXQNsNzDF+dO3cu9TBQLma88N2qtGDRPKza7LjNnBuzoiEpIcWRw7AUvQ99ODfjBftMlDGNAz564yj/ec2Tn6R3UUqjJu1V9WaMOcssVWFIQejXScaBWY41B7s9ODN+6E3SMMDxURrHsOQ85smBCn3eVn8pjb60bebcmCnNi9tLTTDCyGEuWhwcHC7Uj4vmomXiGnPV0WQ1YeQvP+IwZxvKaV6QAZyoMU8eQVZK4SRfOGRJlNLoSjvKrdk8kAlziI0PmkE4DRmhx7pss+f8tGEz55uN678ZK/2GYcyQUIkv0+w58drMuTEz3MMwg2AZMWPFsj3DPQxjjDFVWGEYY4ypwgrDGGNMFVYYxhhjqrDCMMYYU4UVhjHGmCqsMIwxxlRhhWGMMaYKKwxjjDFVVM/0NsaYTcUzvQ+xaRAzCJYRM1Ys2zM8JGWMMaYKKwxjjDFVWGEYY4ypwgrDGGNMFVYYxhhjqrDCMMYYU4UVhjHGmCqsMIwxxlSxsMJgoXwmtuDevn2b/NjK7++//05+4uHDh38s2h/D4whjjDHmbDHITG8q+JcvX6b9g4ODyaVLlyb//PPP5NevX5M7d+4kf0FcoHCC8NevX5/s7u5OHj9+PPU160KfjBizrli2ZwwyJHXx4sVU0UNX74CexPb2dtr/+vVr2hpjjFkPBvuGQa8AZfDhw4c/hqHEz58/J0+fPk37r1+/TltjjDHrwaAfvV+8eJG2T548mXz58iXti+/fv08uXLgwuXbt2mRrayspFvyMMcasB4MqDL5J7O3tpX2URuTdu3eTu3fvpvFAvl/IzxhjzHowqMIAPnLv7OxMj2bQu+DDEU4K49WrV2lrjDHm7DO4wgANTQn9bivoifC9A8WRnzPGGHM2Wfi3WuZU8D0CYhj9Vnv+/Pn0uywwXEUPJP6GC//973+TE/RQcqVjzjb+9dCMFcv2DK+4ZwbBMmLGimV7xlKGpIwxxowPKwxjjDFVWGEYY4ypwgrDGGNMFVYYxhhjqrDCMMYYU8VCCgNbUPxyhosT8JiDIX+vbWGMMeNg0PUw4hoXKBNsRXlti82gT0aMWVcs2zMGG5JiPYxbt25Nj4wxxoyNwRQGPYnLly8X18KIS7narLkxxqwfg370xv4TZs35hhFhyOr+/fupW4c9KdbDMMYYs14MqjC0HoaMDYqPHz9Orly5kvYxPojCyJWKMcaYs82gCgO0HkbX31EMXZnNAVnQcGRpyNIYc/YZXGEAQ1Pfvn2bHk3Sx/CoQDjHUq1mM0AeGI7E+a85Y9aXhRUGH7P5pTb/mP369evp3kyBqJXJEJUxxpj1wuthmEGwjJixYtmesZQhKWOMMePDCsMYY0wVVhjGGGOqsMIwxhhThRWGMcaYKqwwjDHGVLF0haG5F8zXWIRSPKzDgX/f7HHOE44JhOyXDCBqjY+2mepc51nqJyMan4zoeeNqjVISLsqByjbG3RZv9Guzd6ZwxK19Y0yAeRh9VAb7g+3t7enev/9ubW39u7u7Oz2aj1I8BwcH6Rj29vb+3dnZSfs5+HOe8DX3UoorpmeO0/VcKa/9/f20z3PNy5PnWvtsiSeGU7nmtMUrOSCOmAeO8Y9wjfJsNpuT1n9jZCk9DFpwtNjev38/9ZlMnj17Nvn06dP0aD5K8bBA04MHD9I+NqxKM8hpLZ4/fz4ZR2zueeprVgXmQGQK5tGjR5MPHz6kfVr59A4oFxwmZPqMUmL1OJqdefr06R/GLOeN982bN0l+IqRBWsaYGYMojNjVx1EpYw4kogo7Eq/DKJ2GFrpe7hgPiuPq1atpH7g+vxY/Kigs6DLUoKERoSGtrnRRfpxHQQnC4ke+24avTDuUHRU8fPnyZXLz5s20DxcvXkx+JXjm+SJdNBKaXkQqXy0TXIoXZXX37t0UFkUDlB3+bdQoMGM2iYUVBhUwLxZKQq4NXth79+5Njw6h8uBlByp+Kvf9/f1Ow4Rt8XRBS3F7ezvFS08l9lZQWNi8Is+cb2tRqhIizI8fP9I+0CpV3j3eXQ8VsHqF80LZU/lHkCHJkZRACcJJRpEx8nLjxo3k30afAjNm01hYYVAB08pTa7sElW2bIuBlpbKm1UeF3WfFthTPSfj69WvqfZB30qfSySt/FIoUVGyJUpnQUkbRRSVkukHRntRibVTYOcgRDY550FCUeou4vPy70jRm0xhkSEotN9CLF4dp6IXkQ1SRX79+pcq3r4WYx8OwQ2wBUvnPq0x2dnaOWp24Umszh0qP8HxTIV+mHxoUsXeIso3ftfIhxpy8d5GjsquJl7yoAUAZ7u3tJff8+fPkJ/rSNGaTGPSjtypRnCp2FIcUAcM7+Zgwx58/f05DRwxtlSrftnhu3749efXq1ZEflf88sAogptnVqqQSyVuYVEJUKECPRJAf8kDvIn6ENe1oaA+FzjPmWbPPs+MYx36XwqfSL7X4iZ/hJeiLVzIYGwd8G8shrS4FZszG0VTuvVQG+wN+TeRaOY4jBweHv7nKX+HiL4/QFQ+/bOZ+kXgtYXWs8Loex2+X/EoZw4OuIV8Kh4vHmw7PoQTPh/PRUfYQn7f8uqAsFI5fYXVtXgaleNnP5asUVjJiNhvkwhzi9TDMIKxKRugd5L/WLgO+h/D9qqvHYzYD138zBh2SMmbZUIHzk8UyvxsRN2lYWRhzHPcwzCBYRsxYsWzPcA/DGGNMFVYYxhhjqrDCMMYYU4UVhjHGmCoGURj8VcKHIVwNTNrCzUMpDSZmyZ/9Eky0Iwy/S7KviWRtEKbNzITi6ErHtLNo+UUIF/+SoqzyuNvijX6avCcoW4Ujbu0bYwL8JdVHV7CutQ5KEJ8mxdXQlYYmcuFKE62Y4KWJXYRRXCW64lJ65jgnlZGa8osQTwxH2baVR1u8pE144oh54Bj/CNf0yYnZDCqryY1gYYUR4eXsC8tLSwUyj8KIxDTyF5+4217yedOLlUyOKiJznJPISG35RfJy4Zj44nWleEsKA/82SjJgNota2d4EBv2GgW2e5iWbHv0JwwCy99OGhhYYEtDwTz50FdPA8GDfegrE8+TJk+QUXxySiMMUpWEyhq84T1wR/JRXU8e85RehzLwehjGnx6AKg5era62DtpXNIph7oDLhZeclb3oFf5jC7ksjByOIxINrFGSKr2ldTs8eVgr441Aq+dg1x1QunEfZUTkBlVPTWk3nMGBo6pi3/CJU+rn1WBQQjnKREihBOJU1s7jJi9fDMKaeQRVG11oHVLClllwEpUHFjaXQtrgWWU8hB2VARaMeBkSLtJAvA6vWMdZNaa1SoVABmTq8HoYx68tgCoPhnLjWgYaUcJzDkBuVLccaImobyuGFJVw0Oy7yNGrWPeiDtNTqxHX1gCK0UKUouCfTz6Lll/cuctRTqImXvHg9DGPmYxCFobFjKlEqeV5GhoJUCdOiZN0IHWuIqG1RJYaI6GXw8qo1D21psE9YjnHs41eLKhjFTUtT++LChQtJuQFpxCEp8sC97ezspGtNmSHKj0rf62EYc4o0FXgvXcH4w4Tz0TWV6vRsO42yaP1rqVEQR9fzF4vi60qDP15yv0i8ljjjMeHj9aQPOtafNLqG83L8baM86rpNhudQYpHyy+FZKxxloGtJI1KKl32VqyiFdbkaQC7MIbZWawZhVTJC78DrYZhV4vpvxqAfvY1ZNlTgXg/DmNPBPQwzCJYRM1Ys2zPcwzDGGFOFFYYxxpgqrDCMMcZUsTKFwYfEeecqMHaIyz9w8s89/n0ze2WbigmC7PNPfhv4K1wO1/WlY4wxm8BKFAaK4sOHD9OjOlASfGjC8QslE72Ayl22nZih21bJA/6cPzg4SLPGiaNkMwh/Jgq2wd8yxhhjBlAYtL77fnHEZs92MPhXAzPDBRW/TD3ktp1KFTqKhdm7KAP/4WCMMYuzsMKg5U6LX8NH+fANPYNodFDDPzjOEZ79ruEqVfyQ2wXi+vxa/OjRYMYaZYYjDaEhra506aFwHgUlCIsf+S71bIwxZqwMMiTFBCcNH9HiV6WqbwZxKIh9homAip/KfX9/v3OSFBZho9G6PlBi9GiIl55K7K2QJ2bwklfOM2s4R3aPCBNtF9FTUt51b8YYsykM+g2DVrfWl8AoH63zNlPWKA0qa3oAVNh9M2qptIeadYv5cnofKDXSRwHklT8KRQoq9o6wXLq1tZUUXVRCxhizCSysMDTcg8NaaLTxg5VXndMQkVrvv379SpVv36I3xB+t2rK4UlzUhnjnVSY7OztHPSJc7AF1gfIjPN9U+r7bmBka3sPp5wVjzPqxsMKIZsvztSTkj9MQkRas+fz5c1Iu9EhKlS8VjRQKiobrbt++PXn16tWRH5X/PFy5cuXYWhtx6EygQFAKEBdUIj/kgXuOitF0k5u6N8asKc1L3EtlsE4wKd0ojGQ+mvhkOpp9XG5ymvM6F8MDptFzv0i8lrA6Vnhdj8MsNvmK4UHXkC+Fw8VjM4NnYswYsWzPsPFBMwiWETNWLNszBv3obYwxZrxYYRhjjKnCCsMYY0wVVhjGGGOqsMIwxhhThRWGMcaYKhZWGHEWb3S5EcJ5YUId8ZSMAxpjjFktg/QwsMfEf8pbW1tH+30KA0UgMyFtMCOY2eHGGGPOBgsrDMw+tNli6jPOJ9Mbxhhj1oOVfMPIh6kYxsJo4N27d4/sMymMjfoZY8zZZOkKAyWhYSoZGqRXwnATy6KyT28Dw4SEwaif15owxpizx1IVhip+DVmxtgQ9ixyGr86dO5d6GCgXY4wxZ4+VDEmJ0roTDEtp4SU+nBtjjDl7LFVhSEFo0Ry+VbStX8GyrjhjjDFnl8HMmxNG8D1Cq+AxLKVeA1stPIQSYUU+KRAWNQL9mou//Dgu9U7M2aBGRoxZRyzbM7wehhkEy4gZK5btGSv9hmGMMWZ9scIwxhhThRWGMcaYKqwwjDHGVGGFYYwxpgorDGOMMVVYYRhjjKnCCsMYY0wVVhjGGGOqsMIwxhhTRbVpEGOM2VRsGuQQ25Iyg2AZMWPFsj3DQ1LGGGOqsMIwxhhThRWGMcaYKqwwjDHGVGGFYYwxpgorDGOMMVVYYRhjjKnCCsMYY0wVCyuMy5cvp4ktckLHf//999RneSitf/75Jx2Tp4cPH6b9RSC+GK8xxmwyCyuMb9++Tba2ttL+wcFB2gL7Ozs7k8ePH099lsfu7u50b3G+f/8+efv27fTIGGOMGGRI6tmzZ2n77t27tAX2X7x4MT1aLSixk6Z969at6d5kcu3atWQSgK0xxmw6gyiMO3fupO2rV6/SFi5cuDDdO2y1a9gIx7GIQ1r4M5TE/l9//XVsX+Thc3QN2zxdHL2HUn5Ih57R3bt301CazmtIKvppqC3mUXnzEJYxZowM9tF7e3s7VbZUllTA58+fn56ZTJ4/f56GrTRkxTFQ2YIMe+W9kryXEMMz3BV7A+LRo0fTvUMYriI86ZNHlFspP5cuXUrbvb29NJQWh7q4rydPnkz29/eTYx8/5fHDhw+Tjx8/pv03b96krTHGjInBFMb9+/fT9suXL6nij8M4VKpUpvrWIfCjVQ5U6n3fO2L4ixcvpgq/rZchUADESW+AsE+fPk3+pfzcuHFjuvcn3BecO3cuOZAfoIykcIwxZowMpjCuXLmStnFYStASjy36CN8blgkKhd4AFbqUWFd+hqBLiRljzLoymMKgda1hqatXr059D+GjOBX079+/pz6HMKREeCpw0JCTyCtewkvB/PjxI8XZ16pXnPQq+H6BK+WnC90T1+i6/D6NMWbU/FtBZbB/9/b2/m0q4unRjJ2dnRRHo1DSefYbRZHOsS8nFF5hcfv7++lc9Mvj4Jyuxf33v/892pcjnlJ+cArHvWifMLC7u3vkxz7E9OK+8rspcM/GjBHL9gyvuGcGwTJixople8ZgQ1LGGGPGjRWGMcaYKqwwjDHGVGGFYYwxpgorDGOMMVVYYRhjjKliIYXBxDp+OcNFk+BMxJN/PhnPbCbIR5usdIF8yfAkW10fiTKoiZ7RT5NCBfKocMSpfWNMBczD6KMvmCasaSIdsK/JbWb89MmI5EOTI/tg4mOcMKmJkMgaEy4FYRSvwhOGiZdcE8NyjH+EazZtkqWZjxp53RQGG5LCsmub9VhjaMU3FXMy44Jjv69ljzFLmYHBgKTsgGGNGMvAQO8BY5SKF/nLexQRrAjLFL8gDRnONMZ0M5jC4KXm5S0tyRqHFDwMsFnI3heyQdlTscuvDSr9UuNDCgewFnzz5s20D1gwxg+lwpom169fP7JQzFBUbvpe9CkaY8whg370xsCf1omI8LLSimt6NGmtCb3wZnPAnDyyQeWsNURKUOlT+beBbD148GB61A5KBVnD0TPhGkzXl5SUFI0xpptBFQYvJAqBll2EykLmzxkSQGG4RbdZfP36NS08dXBw0PsjBJaISzCs1LduSo6GopC5Ui+3K01jzCGDKgzgxdzZ2emsFLQIktkMqJxfv36dWvu0+mlAdDUYSr0LhrTu3bs3PTo0L//p06fp0STt5ybnuUZDUZi1p0GD0yqLopSmMWbG4AoDGHKICyMxDBEVCOfiinxm3LB+iD5U10Cln7f49SsucoMCQhGwjyxxjMvlSkopDkXFpYMFaXltE2MqaFp8vXQF47dFzuP4tVHwq2L8rXZr6891LMx46JIRQBZU/vz22gfyIjnRb9vR6RxylvsB+/GXWiiFJS1jSiAv5hCvh2EGYWgZoXcQf61dFgyParjMmDZc/81YypCUMYtCBc63Ds30XgbETRpWFsbU4R6GGQTLiBkrlu0Z7mEYY4ypwgrDGGNMFVYYxhhjqrDCMMYYU8XCCoPfEvkolDub/jCR0noWUWZwucmONgiT/z2l+PO1Nkr+kRiGuJWXXIaZfKr8cU1NXo0ZEwsrDP6T397eTnaC+JMAh+kFYwSzsrEai2xgNkaVPRW0ZEbn+qASx3LA+/fvpz6HSkcGB6P58pJ/JA+DyRDkF3nGlIgg3WjAkPRt5dZsHM2L0ktfMGbUMovWbC6VopRmWJfC1s4AjyB7bQt1lfwjbWHIQ6MwkjxzXpTy5lni46dWtjeBwb9h5EYHNWSlVqWOaV0Sln1dwzmFM+OEFnpTyU6PZjC802cAUL0LwTX0cDE6GOWo5B8phfFaGsaUGUxh8ILx4r18+XLqc/iiYXahUUzpGCUhUw90/zFS2LTwjioKhgDiUIMZH1SubetZvHv3rtcAYL5OBibTaWRouAvZI/6Sf6QURsNTOGaA4+e1NIw5ZDCFoW8YcRwaswtSJFgr/fz5c/InjD5CYin01atXad+Mn9J6FshBn4mO3ILtz58/04p7ug65ovIu+UdqwoDX0jBmxuBDUvlqagcHB0ctNp2jxYby4CVkfQPC5C+hGR/5ehbzkg9ZXbhw4VhlzXn8Sv6RmjBeS8OY4wyuMCKM78aXS+PErL7HEMCvX79SC4/WHee0Kp8ZH+pRUt40DqiMBedoRPSRr5NByx85UmODnioyVPKP9IXREFYcivJaGmbjaVr+vXQF4y8RzuP4uyRH53D5GgT6Q4Xr/LfJekP5lmgaBMfkIJcFzteCnMRr+ZtJcUb5a/PnOo71R1/pWsLFP6Qghs3l2IwbytwcYmu1ZhBWJSO0/FexTkYNfDT3Whrjx/XfjKUOSRkzNFTOy14nowbS91oaZtNwD8MMgmXEjBXL9gz3MIwxxlRhhWGMMaYKKwxjjDFVWGEYY4ypYmGFwa+FfBTSxKwc/ibhvCbt1aJ4zXhQmXaVKxPp4h9QyE0uO0z6UzyaeFeCsJokSFhdp4l5gjQUF+n3xWvMJrKwwuB/+O3t7fQ/eg4vHTakMDCYmwzpg18WzXigQUGZ8rdJ6Y8TKvG41gWVOLOxI6rIiQO5ys105Dx58mS6N/FaF8YsyCBDUhhxg/wFwwIpZj+MwSrs1tZWZyWcT8iTNeMcGS/EJEeXHScUTtv1OTIwGCEf5McYM2Owbxi8XLx4JagoGArQ8AL7DFGI0nCFrothzfpB7+Lg4CBZL24bvqSc41oXJaJtp5LlWyC+3D6V17owZjEGUxi00OIwEi9aNMrGjNjY2mNYQPDSMkTAMAPDW7FCkT94XHl9oaLHoTRUWUfytS66QA5oRDBcFY0YRtp6DaSvITHkUUolKqEI+fFaF8bMGExhAAvj6AXmha01m4Ci0cvN+HF80eOCSr9//57umXWFyrmttxit0Pahip8GSNtaKjQ4Sr2GiJQKikO927xRMk++jBk7gyqM27dvpxeYl27eNQLce9gc2lr0J1lTojQcxQ8YfC9BAfDRG6ehUEHDxmtdGDMfgyoMKgLGfXEoj5y4QE3s6hOeD+SiNMxg1h9a/21rX+RrXdRAz6Dtuwe9Ug090QvBxb/09F0iKi6vdWFMBc1L1UtXMNYD4LzWBWDdAK0lwJZzONY80HoEOJ3TWgjyxxFO8RIuxmPOJl1lw1oTKr+utS8o87jWRFPR/3Fd9JOcgWQL+YsQHicIF68Dr3VhukAuzCG2VmsGYQgZoeXvtS7MWcP134xBh6SMWQQqZ36A8FoXxpxN3MMwg2AZMWPFsj3DPQxjjDFVWGEYY4ypwgrDGGNMFQsrDCZEMcaXu0VtPzEXg3j0z7wZB5RrnGcjMx+42smbhOszgV6Kt80/+uXyRrwKZ7PnZtMZpIdxcHCQPgptbW0d7fcpDF7MNiN0glm829vb0yMzFqK5cWDiHTKDa5uEl4PcEK7LBDqU4m3zt9lzY+pYWGEwg7bN1EO0AdVGfDHNZkDlzqxrQcVLwwL5kZWAvsq4xgR6Kd5502szYGiz52aTWck3DHX31eug4mBhJUxNs89LqzCn/Q++WQ6UcW4SBPMwWksF+qzDEod6BV2U4i352+y5MXUsXWGgJOj+M0zFi4ZCoFXIcBPDAOzT22A4gDC04DxOPD7aWuvzQuW+DGOA9DaQPZzNnhtTZqkKQxW/XjxabPQschi+OnfuXOphoFzMuKg1N97HqkyN2+y5Me2sZEhKlFpsdP/pfdDC48O5GRclc+NYgv306dM01CTtd1mHre1dlOKtSc9mz40ps1SFIQWh3yhpsbWt8Y3dnrhanxkXJXPjDP9oCBLHfpf9Jir3mpZ9Kd6+9PRdIjZsbPbcmEDzEvdSE4wwctHE9MHU7DQumovG5DR+mK3GxTDylx9xmLMN5VQD5Y4TJdPiJZCPGE5yhJMJdCjFW/Jn32bPTRuUvznExgfNIKxKRugFnKYJdH7isNnzzcL134yVfsMwZlGoqE/LBDpp2uy52WTcwzCDYBkxY8WyPcM9DGOMMVVYYRhjjKnCCsMYY0wVVhjGGGOqsMIwxhhThRWGMcaYKqwwjDHGVGGFYYwxpgorDGOMMVVUz/Q2xphNxTO9D7FpEDMIlhEzVizbMzwkZYwxpgorDGOMMVVYYRhjjKnCCsMYY0wVVhjGGGOqsMIwxhhThRWGMcaYKqwwjDHGVLGwwmBhfCa2tDn4+++/j/bl//bt23Q8JDEdY4wxw7Owwnj//v1kZ2cn7R8cHKQZkbjt7e3kF9nb25vuGWOMWTeWNiSFIoHHjx+vZFr9qtIxxphNZXCFwXCThpz++eefo2GoyNOnT4/5f//+/ehY+wwxweXLl4+dAw0/KVyeTn7eGGPM4gyqMLa2tiZ3796dHk0m165dax2aevDgwVFv4OHDh5NLly5Ndnd30/GtW7fS/o8fP9I5ICzDXpyDV69eTfb395ODPJ38vDHGmMUZVGHwDaPmO8WFCxfSFgWjXoN4/fp1Gl568eLF5OPHj6mHARcvXkzxEx6Fc/369cmvX79S2Jy+88YYY+Zn8CGpO3fuJHdSzp07N90rgxJAedCbUS8k0nfeGGPM/Czto3cf9BSo1G/evDn1+ROGoL59+5b2GaKiR8LwFb0Otgw50QvJ6TtvjDHmBPxbQVew7e3tdF6uqaSnZ/5N+/Lf2dn5d29vL7mm4j/yg0ZxHIUjvojC4ggHXCc/4svTyc+b5cOzNmaMWLZneMU9MwiWETNWLNszTm1IyhhjzHphhWGMMaYKKwxjjDFVWGEYY4ypwgrDGGNMFVYYxhhjqhhEYURjf0zIW5XBP6XLmhzm7MOs+7aZ9yX/EsiYyjyuxxKRn1xugkZE45ZAOB1j1DJCHhUP6ZbiNGasLKwweGmePHmS/lPGMRs7Mk9FMA+8zJ8+fUppMlvcVmnPNsjBy5cvp0czSv4lKHcsAGA+nzLH8jEysLOzc6REsJYsedS5NgiHJQCFg+fPnyd7aFgJePbsWfID0r1x40ayIACkTz5ypWLMmFlYYfz+/fuYksDch1hmJf7mzZvJ/fv30z62o7BQa84uGJOUReJIyb8EZS5zMZQ7lorh0aNHkw8fPqT9NltmqugjKBtkt6bSR97yeMmHZNCYTWBhhaEXVl16XkxeZFpv9DxoPcribOz+qzvPyyq/eA6n4zbFQ8vwypUr06NDPEQwbtS7aAO5y3u3gExg6bgNZIgGDpaNtYYLigejlfihUIBeEP5tuJdhNolBvmHQ0uJlpXLXsACtMVqODAdwnheSl4uuP/7v3r1L4Wih0f3HnzUt2OflV1gcisfKwHz58qVY+VNpY9Y+Bzm7evXq9Og4yBkOpSHlwLHkjsYQ8cahqBzyQ76M2QQGURiAUuAlY1ig7bsFCoThBxQKCkDEFiMvJWtYoBx4idXDgK9fv6at2VywWFyCISN6tjlco15wCeROveAcDUXFnnDeeOnKlzFjYmGFwYuk7jxQ0beZFNcLR0sujlnT1af7rxdR48T0WNTSw+XjxygaKRG9wKVWoBkHpd4FQ5b37t2bHp2MNtkhXg1F8QGcj+E4PoxHSvkyZmwM0sOIy7JSibe11ui2oyjy1h69ESkF/jwBvbxSRLlSAioIVucDhh3ahiPMuGBoKW/NSy6QKxoO8XsX5xhO6qMtHDIHUZGcP39+ujeD/JSGvIwZHU1F3UtXMNaiYM0Jwsg1vYyjcxw3vYVja1ZwzJbr4toVOK2HkYdvQ9fma2iY1UM5dNE0Fo7Kk3ITJf8SyILkK5cdnM5BHh/nCJPLbFu4XKaiPMY0SrJpxgNlbg459fUwaN3F4SZaiG1j0eZss0wZidDyj7/Wnib0pOnl9n0jMevNqmR7HRjso/dJ4OXXsJLwB0TTBZUz38j0N95pQfrkw8rCbBKn3sPgxdOEK2i6+/54vYa4FWbGimV7hpdoNYNgGTFjxbI941SHpIwxxqwPVhjGGGOqsMIwxhhTxSAKg19hGefD5ZOnlgFpKD2cJlmZsw2TNHOzMbns1EA4/SVVup7z8u8iGsSEKFu5XJF3pUH8tfk1ZiwsrDB4aVa9HgZ/UekjFH9V+dfGsw9ykK97oQqXssQKQG5yow0qcczCYBWgdD1KpG2djBzmAPFrLOEkT14Pw5gyCyuM01oPw6wXpXUvNEkT8xo1NpnySXtt1+OnRkRcJyPH62EYMydNy6qXvmCYR8jDRNMLMp+gcDiZV4gmF+I5nI4xH9GGwprTh7Log3Ismf8o+UeQlZNcL/nLiXKGvMpPckd6QNwlOeOcwplxUiPbm8Ig3zBoadFSY9xX3X9aY7Qomxcqnaf7rzUu8Pd6GAYoV+SG4aq+Hmnbehh919N7KBmmRM5wjTLwehjGVDDYX1IoBV4yr4dh5kEVNI2IvmV228zG9F1fWicjQhxeD8OYfhZWGLxI9B4EFf0q1sMw46LG4GTXN4626+lx1K6T0daD4Hqvh2HMjEF6GKexHoYZF5Rx7G220bYehsivl7wgbzREuoa7COv1MIypoKmoe+kKxge/+IEbpw+EnOOYj47a1zFbruOjofxxNethEH+8hrDmdKEcumgaC0flpQ/U0a92TRNkQfJVuj6XKRzXSG5ymVV+BOG8HoYRlLk5xOthmEFYpoxEaPl7PQyzSlYl2+vAYB+9TwIvv9fDMPNA5ez1MIw5HbwehhkEt8LMWLFsz/B6GGYQLCNmrFi2Z5zqkJQxxpj1wQrDGGNMFVYYxhhjqhhEYfArLON8uL5JUkNAGkoP93//93/HjjXpypwd+H16kfKhzPVnFFvFFSn553gNDGNOCB+9++gKpslQgn0mVIl8UtSQkFacRJUfm9XRJyOa4JbLSw1MmtP1yJYmaiJbmmBX8s9hwl4uI4THn+vjdRzjHyEfSsdsBvPK65hZuIfh9TBMH5iLkcVYfpluKui5TL3EiXqltS5K/jleA8OYk7OwwtBLqu49FQIvLxUCVmkxOy3bUnEoQF17Xlz5xXNxmMCKZ735+fPnsQmZGOvDrwbko2RjClmLjRVR8gcm29GoweCllBYKBnto+MnMOUNRMjyYQ35OMqxmzLozyDcMWl28oFTuGmemZba76/UwzKHRwLg8K8rjwoUL06Nu2tbAEFTabWtdlPwB2cKhNLwGhjHzMdhfUigFXjivh2FyqIRpOKg8UR5XrlyZnu2my1RMaa0Lr4FhzHJYWGHwUsXxaCp6r4dhcmgsUI70IOlJllrvOaXeBcOUbWtdlPzbaMsD12soymtgGHOcQXoYXg/D1EA50jhQOdfQtgaGZAFZopGhb1wl/zYI6zUwjJmTpqLupSuYfj0kjFzTyzg6x3HTWzja1zFbruOXRvnj9FtjHj5C/PGa//3f/z12zLVmtfDcS0g+Sr+69kH5S6ZyecFxruQvWcnllPARwuX5izKo9CGXRzNuKH9ziNfDMIOwTBmh5e81MMxpsUzZXjcG++h9EqgIvB6G6YPK2WtgGHP6eD0MMwhuhZmxYtme4fUwzCBYRsxYsWzPONUhKWOMMeuDFYYxxpgqBlEY/NlEtw3X9//7EJCG0sPl5s1t7vzsEcsDRxn2QZj4oZs5O7kVgdp4ox0ziDKUywdpKB7Sr8mrMRsB3zD66Aqm/9wF+5iaFvn/7kNCWvH/+L5jszyiDOQw/yGCTPSVC3Mg4nwHzbOI8lQbL+Fyf8LiTzpx/oXma0TIB/5mM+mS7U1j4R6GzZubPtrMuvT9CZfPu8C0SDQpA7Xx2qS5McOwsMLQP+nq6vPC2ry5KUG59tlhQiZKJs1LdMVrk+bGDMMg3zBogdGCo3LXmDOtNFqETdc/nedFtXlzQ7n32WHqMmleoite5AmH0rBJc2NOzmB/SaEUePls3tx0wUz+vpnSJ5ntXxMv8tVmGBNs0tyYfhZWGLxg6uYDFb3Nm5tFWKbp8LYeBEOeNmluTD+D9DBs3tzUQBnmJsXbaDNp3kVtvG3hkC2IisQmzY0p0FTUvXQF02+IhJFrehlH5zjWb4k6zzFbrtPvknJDmDe3ufPVw3PuI/4S2wdlLjmCprFxVJ55PPmx5COXzbZwNmlu+kAWzCE2b24GYWgZoeVvk+bmLLDM+m/dGOyj90mgUrB5c9MGlbNNmhtztrB5czMIboWZsWLZnmHz5mYQLCNmrFi2Z5zqkJQxxpj1wQrDGGNMFVYYxhhjqhhEYfArLON8OGZrL9tYIGkoPZxmkcsJftmVX27mwayWWGYuC2PWk4UVBi8/tqH4KITbCqbOoc2u1KLwF5U+QvFXFb88stWxYH4Hs8sx8+A/r04XbIZRNrhoP8wYsz4srDDOynoYKISdnZ1WI4W2Q3W60ANk8htlhENhyCSHMWZ9WFhhaEKThoKoEE5rPYx79+55IuAZBDtiN2/enB7ZVLgx68og3zDOynoYKC/SUljSRIkYY4xZnEEUBpyV9TAePHhwpIx+/vxpkw7GGDMQCysMhpRoyQsq+tNcD+P27duTV69epX0PR50NMAv+6dOn6dEk7dtUuDHrxyA9jLO0HgbXkj7xejjqbBCHCnHsu+dnzBrSVNS9dAXL1xzANb2Mo3Mcs5ZAXGeAY7ZDrYdB2IjyY1ZH3/OO5Sn5MGYdcF0yw+thmEFYpowYc5pYtmcM9tH7JDDU5N9gjTFmPThVhaFxbDS4nBbjN8YYc7bwehhmECwjZqxYtmecag/DGGPM+mCFYYwxpgorDGOMMVUsrDCYIKcP1tG1Td6bB62xwZ9UZjxQrtGYJBP5JDPsl+Cc7JQBcpeboCnF1eYf/XIZI16FI80YlzGbzCA9DMyB8FEIcx7a71MYfbO3mYuBMUIzLqIdMcCWGDKDi3bFIsgK52QJgAodK8g5pbja/J8/f57WSdnf3588e/Ys+QFp3bhx48jaAGlyjRsuxgygMDAoqJcrope7RHxJzWZARR/tiFEJ07BAfnClihmLxpgTEchcjAdKcdWmId68efOH3TLSJg/GbDor+Yahrr96HVQcWLXFBhX7vMAKE4cdzHigjGm5R2rWyeA69Qq6KMVV8me+D/KH4UsMYgKyWJoH5F6GMStQGCgJhgIYpuKlQyHQQmS4iSEB9ultMDRAGBmpM+OireVeA5U7lfzQ0NtA3nBMIJVCw78NL/pkzJIVhip+vYS03uhZ5DB8de7cudTDQLmYccG3qpPO4F+VqRgptNjbzRsuNltjNp2VDEmJUuuNoQB6H7T2+HBuxgX2wihXKmE+euMo85p1Mmp7F6W4atLgry0pNHq79HxxfBiPLKOnY8w6sVSFIQWh3yhpvbFkaw4LLrUtumTGAT1IDf/wsRrHUGTNOhlU7jUt+1JcfWnou0RszJw/f366N4M85IrGmI2jeYl7qQlGGLm4PsVBWLsirmvRVBrJj/Uw4poYhJG//IjDnG0opxood5yoWScDmYjnJDs45ESU4ir5s6/1V0QpbJRds1kgC+YQGx80g7BMGaEXkP9au0r4cYNhtbz3YzYD138zVvoNw5iTQEXNkOVp/HJNmqRtZWFMozzdwzBDYBkxY8WyPcM9DGOMMVVYYRhjjKnCCsMYY0wVVhjGGGOqsMIwxhhThRWGMcaYKqwwjDHGVGGFYYwxpgorDGOMMVVUz/Q2xphNxTO9D6lSGMYYY4yHpIwxxlRhhWGMMaYKK4wFYb3qeb/x6Boc5rPZauU3szg8U5aAreEk5WfMpjK3woiVXf6ixQX0cW2VIP7EkcMLHq+tfeFPmzt37sz1QYxnwmI8XMO60R8+fJieMUPBkrAsAVvDvOVnzCYzt8LQC0ZlB3FRGxaZ4dz29nba5ovOaG1vKswcXvCDg4O0z7b2hV83vnz5crR+NM9S93yWOY2Fi+ZhyPyx7ve6NFaMWTULDUmxmD8tZCmCPj59+nTUqubF3ER+/Pgx3VsPasv2tKDHNmQv7fnz59M9Y8wfND2BE9FU/GnBfC3Iz77IF9YHznMNEJ7rclh0n3P54vtt8QHx6RbY5vHGBf0VTuzs7Bz5x/g51jkt/J/HE++V9BQOiIvrlTec7ifGgSOM7llx5mnF+9E1pMG+8p0fg/IV42M/PxaElb/uJz6jGD76x3tX3Pl18gM9l5hXoWeRXyPiOeKJzxinZ0We2M/jEzrmfCw/PUe5+ExIC3RvsVyM2RQWVhigF020VQbx5We/q8Jg20es+JS2KhDgfEyDfR2TvvKjNAmvCiJel+eJikLhlZ4qHFUmOMVPXNqHmDbE9IHwqpyUFsTKi7C6Lj+O+cLFe86PtU947Sse5SGGA/IUj8kXLuYnVqbEo+cj4v1H8Ne1ugfiBfb1jAijOBVOkLc8D/Fa0PPStTF/XB/zx3485roYtzGbxOxNmxNetvgS8uKpIokVCvCSxZeO6wivykBw3OZfIq8sFC+QHvu5A7alNDhHvCKvMIAKRn6x8oK+Cic/1j3HZyni/UCet67jPF99xxH8FQ95jeWZ51V5ZKv9/NkSnypZwsQ8l4iyQPhcpgTnCBeJ6QH3EI9j+vlzyMsvLx/C5/dnzKYw2G+1zQtV/J7x7t27ycuXL4/+gLp+/fqR/zJpXnxqkmNu3m8nbeFv3bq19G8wfMjVc1oV+gOuqRCnPsdpu2f92PDr16+0bePZs2eTV69epf03b96kj/1d8NG5qcSnR5PJz58/p3sn4969e5MnT55Mj+aDHxSQI/INfIPSTwvGbBqDKQwqjqb1lV7Mb9++TX0P4SXLK25eQlUiyyKv4KiI9LL//v07bfsg/MePH6dHM5ZVaej34qdPnyYlvAr0O/Tnz59T2cTKOqJ75k+vnPPnz0/3/kR/g7X9Th2hsUE+bty4cUxpXbhw4Q+Zmgdkk3sifdLoU1g5KBwaPFxP3ozZVAZTGPD48eP0S22EF5QXLufRo0epUljWXzikmfd4pEBQVvfv30/7gH8pH8ST55PKg/wvA+JGUcRfkslf25yWoaD1zDPJf2Wmgrx48WLaJw8cE45GgZ4lfpR5/gt1Do2Ju3fvtsqCoAGxt7fXWqHnZcA+eYiKqlSG8ODBg9bfuXOkFHneeubcG/dI/udVNsaMiqZFOTeM+XIprm1sWX5sFS4ft5Y/jviaiuiYH8fAubY0NHYtxxhzPG4LE4l5Iw2IYWN+87ibyiv5M54tP+VTx+Q/3lN+f7i2e4jh9Jy1lcuvy4+bSvlon2vzfObH+f0pPfx1Dj8R86iyKT0jwXGMo408X9oHrtcxjrBCfkqjLYyuJ58iTw/0LHOZw5/7NmaTsbVasxLoDfDNil7oOkJPit5MX0/KmDEz6JCUMSWYEHf79u3p0frBcJaVhdl0rDDM0qBXwUdsfche1o8Cy4JehfI/VlM1xsyDh6SMMcZU4R6GMcaYKqwwjDHGVGGFYYwxpgorDGOMMVVYYRhjjKli6QoD20jLWLENMxCXL1+eHs3AT79CknZbmEXQr5ZDs6x4+yDdoZ+RmUGZ8oyNGQMLKwwZy5PD/o7s/LDFNtIyYMZwbpAOxaT1sremBvQWMVrXBraEhv4TmWeGnaJVQ0W2inSjfORONqnGCrJi+1NmNDAPo49ocyfa4uE4tw8ke0oKh/2d3C7PsiDd3IbRonAf0SbRspANo1VDunkZLgOeYS4Huawsg1XJ3jrjZ2Rqqeph0JpvXuq0r3UP6FlA3oJ///59sjjatT7CMlhWS5W1HMxy0OzpNnPpQ9BlvdYcQu92yDXRzbipUhgMXVBxogiAypmhpqb3kI5z6IKXuuH5EJYqerYcM56OEGvcly3+XKehLuBY30bw1xAUW43JxzAipq00lLaclCHx8DJhzht/IK18zJ/j/FpQ3kHn+yoxXYNT/iCmEdMvPR9QeJxMdUNMo29xIuKM8UQ4Ji7SZj9/Ln1oAS3ZmCKPxKP4oovndQzst+WBY8qN8sM/3r9ANnSO8CI+H1ykr6yVD5UF+0pbYYCtwok8XVzpmSofpEGasZyUL8WndyC/X85rkS78lZeYj5g+1+dpQX5sRsy0p9EJw0oM9TB8gWMIgUvZ7yMOScnEtGAoRCajCcN5hVHcGi7hGH/Oa4gsdqV1HVtoC8Oxhj84r7jJg4adYjpAmPycrgPi13nlgfj0jORA17ehc3oeOiYe9vNniB+0PR+I6ehZAOFi/tmPx5E8LHlQPPizj1Ne4n6O8hBdjFv3hdPzBN2X0HOFvjxE2cshjNIhjMLhH/PFfgyn/VJZK22QH+f75EHxqfyIN+YjQh6UDmGizOTXxHOl+1UegGNdA4ofp7wrHs7lx9o342QmKR0gBBIWnIRfQtsFgibhzJEgAmG0Hymlk8ebv3AQwxBHKR+RPJ78JWBfL2WsvISeFeQvY1t4kYcF8tv2ApK+ngnX5M9HceWO9Ikzhmdf95MT0wE9G/nFfcjDR7iP/PlTPjEOPZ9YhpzDT+TPsCsPuYxE8nhF/nzEvGUNel5cC3mYGGcef1t6IspgDv6SGeLQvZTuN/fn/jmOTmlxLr6jfcdmfFR/w2jCHrlz584l/5OutayuevyDivFsjvGP3eBGoNOfPPirq30SavJK/M3LMT3qp+07zdWrV9M2Dg0NhYYKmopo6lN+PtxHLDMc5rkZoulaTjUS0wGszRLvomtsC8q8qWTScrSrhiFT0ua54TRsVPqrbtllTdnwbClj4LsO+WtDa4oo7zH90vrppftto1E4x+Rm6D8Nzfpyot9qqTgQvtLC+ghjHJuNIKy3bt1Kgti0Rqa+h3FKQKmoNO6KoOPXtJaSQinF20fXutAag83Xku5DFW/byzeEKW/yS76Jn/y1rbldej75fVARKZ+1PySQDmnmkKchmeeZDwk/aPDskEPG8ql4aay0KcRllzVQ2Uv5826RvxLIBnnnPczlgecpxRNpu982WIM/skhDzYyLE8/D0B8uCHeEFwrBb1tZDSFGuPOKG38UhASYyk+ot0ELjJbPSdGLFBUO+6RZWkuafCl99vMXTK3CuD44rbpF8qk09MKTp641t9uej+5DShe0ABDxUCkpHfx5LrFXJ1gHGyWkSlLb/DmdFJ4/PZ7YcMhRRa386q+1XO7ayNcjj3AsWeC5qtKlLOOa5UCFuYyyjpCe5hDJlSDfup82pUKeKOO4fnrpfmNvk/PcH2Wu+ONzMAbBXIimhXNsvJNj0VQEf/jHsI3Qpm0j4CmsjnFNJZbCx/g5D3m8XK9j+bWlTZwxHNdBvD7mIZ4jvjyciNcoTo0Ny2lMWq6NeE2MP79W6eHf9nwgv1fCiniNnnuJ0j3LD0e+lScdR2LY3JE+5Peo8oeYX+UH5Idry4PibLs/zufxinjPuJiXmEaprCF//v/973+PHef3C/FYLuZL4Bfznj9v0s7vuet+5af7jPeveHKZ6Ts248QLKBlzBqAl//Xr1z96b7T623rrXRDXOq+fbs4uJx6SMsYMB8Ne+beTkw4Hrfv66ebs4h6GMWcAlMPW9LuC4Lj2D6V4/V7L9zhjhsAKwxhjTBUekjLGGFOFFYYxxpgKJpP/D/rhoIfsbNqnAAAAAElFTkSuQmCC\"\u003e\u003c/p\u003e\n\n"},{"header":"Discussion","content":"\u003cp\u003eThe aim of this study was to investigate the serum adropin and preptin levels and their association with CIMT among biopsy-proven NASH patients who did not have diabetes, hyperlipidemia, or hypertension. Our study is the first, to our knowledge, to evaluate circulating adropin and preptin levels together with CIMT in a biopsy-proven NASH cohort.\u003c/p\u003e\u003cp\u003eThe global prevalence of NAFLD is increasing with the obesity and diabetes epidemic. In Europe, Turkey has the highest rate (48.4%), followed by Italy (38.2%), while Germany, Portugal, and Spain report rates between 25\u0026ndash;27% [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Obesity, IR, T2DM, and dyslipidemia are major risk factors for the progression to NASH, which affects up to 33.5% of obese and 37.5% of diabetic patients [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In present study, our findings align with these epidemiological trends. NASH patients were either obese (86.1%) or overweight (13.9%), and they exhibited significantly higher WC, BFM, and BFP compared to controls.\u003c/p\u003e\u003cp\u003eCIMT is a reliable marker of early atherosclerosis and predicts CVD and stroke risk [\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Many studies have shown NASH increases CVD risk, independent of traditional cardiometabolic factors. NAFLD may also contribute to increased CIMT through shared metabolic disturbances such as IR, central obesity, dyslipidemia, and low-grade inflammation [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, the mechanisms linking NAFLD to CVD remain unclear. In a population-based study of 407 young Mexican Americans, Gill et al. reported a high NAFLD prevalence (48.8%) and noted 31.2% of those with NAFLD had subclinical atherosclerosis, highlighting the need for early screening\u0026thinsp;\u0026lt;\u0026thinsp;45 years of age in this group [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In a meta-analysis by Teng et al., reported that NAFLD patients have a significantly greater mean CIMT than those without NAFLD (MD, 0.12; 95% CI, 0.08\u0026ndash;0.17; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In our study, the median CIMT of the NASH group was found to be significantly thicker than that of the CG [0.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09 mm vs. 0.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06 mm, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01], consistent previous studies.\u003c/p\u003e\u003cp\u003ePreptin is a pancreatic hormone released alongside insulin, originating from IGF-2, and contributes to insulin secretion in response to glucose stimulation. Yang et al. reported significantly higher plasma preptin levels in T2DM patients compared to those with impaired glucose tolerance and controls (456\u0026thinsp;\u0026plusmn;\u0026thinsp;14 vs. 416\u0026thinsp;\u0026plusmn;\u0026thinsp;13 and 398\u0026thinsp;\u0026plusmn;\u0026thinsp;13 ng/L, respectively), with strong positive correlations with BMI, insulin, and HOMA-IR [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. It has been stated that elevated preptin levels in T2DM may result from increased secretion or reduced metabolism. Similarly, Kalaycı et al. also observed a positive association between preptin and HOMA-IR, suggesting its role in pathogenesis of IR and metabolic syndrome [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In addition, El-Eshmawy et al. found preptin positively correlated with BMI in obese individuals [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In contrast, our study found no significant correlation between serum preptin levels and BMI, BFM and BFP in the NASH group (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) and a tendency toward positive correlation with HOMA-IR. However, participants with BMI\u0026thinsp;\u0026gt;\u0026thinsp;30 kg/m\u0026sup2; had significantly lower preptin levels, consistent with previous studies. These discrepancies within the NASH group may be due to differences in study design and population characteristics; as our cohort excluded patients with overt metabolic comorbidities.\u003c/p\u003e\u003cp\u003eDespite its potential relevance in metabolic regulation, preptin has not been studied in patients with histologically confirmed NASH. There are only two studies conducted in NAFLD patients diagnosed by USG in the literat\u0026uuml;re. Argun et al. compared serum preptin levels in NAFLD patients by confirmed USG and 35 controls, excluding those with IR or diabetes. They found that the NAFLD group had significantly higher preptin levels compared to controls (83.7\u0026thinsp;\u0026plusmn;\u0026thinsp;71.1 pg/mL vs. 56.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1 pg/mL; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Furthermore, in linear regression analysis, the FIB-4 score was an independent predictor of preptin levels (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), with each 1-unit increase in FIB-4 score associated with an 86.37-units decrease in serum preptin levels (R\u0026sup2; = 8.5%) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In another study, Wang Jinjun et al. found that serum preptin levels were significantly higher in NAFLD patients compared to controls (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and were positively correlated with BMI and HOMA-IR (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In contrast, our study demonstrated significantly lower preptin levels in the NASH group despite higher rates of obesity and IR, consistent with the findings of Argun et al. Furthermore, preptin levels showed a moderate negative correlation with both steatosis grade (r = \u0026minus;\u0026thinsp;0.376, p\u0026thinsp;=\u0026thinsp;0.008) and NAI (r = \u0026minus;\u0026thinsp;0.387, p\u0026thinsp;=\u0026thinsp;0.030), indicating a potential link between preptin and histological severity in NASH. The reduction in preptin levels observed in NASH may be attributed to β-cell dysfunction induced by chronic metabolic stress, as well as impaired hepatic processing and clearance of preptin secondary to progressive hepatic fibrosis [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. These findings support the possibility that preptin secretion and regulation follows a biphasic pattern during the NAFLD progression.\u003c/p\u003e\u003cp\u003ePreptin is also involved in the pathogenesis in CVDs and demonstrated that the preptin single gene polymorphism (rs1003483 and rs1004446 only) were associated with increased susceptibility to CADs and hypertension [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Cia et al found that hypertensive patients had significantly lower plasma preptin levels (1930.30\u0026thinsp;\u0026plusmn;\u0026thinsp;268.47 vs. 2182.88\u0026thinsp;\u0026plusmn;\u0026thinsp;325.81 pg/mL, P\u0026thinsp;\u0026lt;\u0026thinsp;0.01), which were negatively correlated with CIMT (r = -0.47, P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and independently related to SBP and TC levels [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In contrast, Li et al showed that circulating preptin is increased in patients with positive coronary calcification, which is a specific feature of coronary CAD [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Yassen et al. reported that CAD cases both with and without T2DM had a significantly higher serum preptin than the CG [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In our NASH cohort, we did not find a statistically significant correlation between preptin levels and CIMT. These contradictory results may be attributed to small sample size, differences of study population and variations in preptin allele frequencies across different ethnic groups.\u003c/p\u003e\u003cp\u003eAdropin is a novel peptide hormone that plays a key role in regulating energy balance, as well as glucose and lipid homeostasis. Prior studies have shown that adropin improves insulin resistance, enhances glucose uptake and tolerance, and supports metabolic control\u0026mdash;all of which are essential mechanisms in diseases such as obesity, IR and T2DM. Epidemiological studies also suggest that serum adropin levels are significantly reduced in NAFLD patients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Recently, Chen et al. conducted the first study involving biopsy-proven NASH patients and demonstrated significantly lower adropin levels in NASH (9.99\u0026thinsp;\u0026plusmn;\u0026thinsp;5.51 ng/ml) compared to ultrasound-normal, histologically normal, and NAFLD groups. Additionally, serum adropin showed negative associations with insulin, HOMA-IR, and LDL levels [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In our study, serum adropin levels were also significantly lower in the NASH group (p\u0026thinsp;=\u0026thinsp;0.02). Adropin levels showed no correlation with HOMA-IR and lipid parameters, due to exclusion of patients with overt metabolic syndrome.\u003c/p\u003e\u003cp\u003eRecent studies have shown that adropin is closely linked to cardiovascular diseases, including coronary artery disease, hypertension and heart failure. Reduced adropin may contribute to both metabolic dysregulation and endothelial dysfunction, thereby promoting atherosclerosis. Experimental studies have shown that synthetic adropin enhances lipoprotein lipase expression, improves lipid clearance, and increases endothelial nitric oxide production, supporting vascular integrity and reducing inflammation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Clinically, Zhao et al. reported significantly lower serum adropin levels in patients with CVD, which were associated with more severe coronary atherosclerosis [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Similarly, Wei et al. found that higher adropin levels were independently associated with lower CIMT in T2DM patients [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Similarly, Wu et al showed that T2DM patients had significantly lower serum adropin levels [(5.53 \u0026plusmn; 1.62) ng/mL vs. (4.80 \u0026plusmn; 1.48) ng/mL, p \u0026lt; 0.001] and higher angiographic atherosclerosis scores than non-diabetic individuals [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In line with these findings, our study also showed significantly reduced serum adropin levels in NASH patients. However, unlike previous reports, we did not observe a significant correlation between adropin and CIMT values. This discrepancy may be attributed to differences in study populations (e.g., exclusion of patients with diabetes or dyslipidemia), sample size limitations, or disease-specific mechanisms unrelated to traditional atherosclerotic pathways.\u003c/p\u003e\u003cp\u003eThis study has some limitations. First, its cross-sectional design precludes causal inference. Second, the relatively small sample size may have limited the statistical power to detect modest associations, particularly with CIMT. Third, lack of a simple steatosis group in the study population prevented direct comparison with NASH patients.\u003c/p\u003e\u003cp\u003eThis is the first clinical study to explore the relationship between serum adropin and preptin levels and CIMT in biopsy-proven NASH patients. In NASH patients, both peptides were significantly reduced and negatively associated with severity of steatosis and NAI, while no association was observed with CIMT. Notably, our findings suggest that preptin may exhibit a biphasic secretion pattern during the progression of NAFLD. These results imply that adropin and preptin may serve as potential biomarkers for disease activity in NASH, independent of vascular changes. Nevertheless, further large-scale studies are warranted to clarify their clinical utility as biomarkers or therapeutic potential.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e: Ozel Coskun BD. wrote the main manuscript text and D.O and C.I done the literature review and data analysis, K.A done tables. All authors reviewed the manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;No funding was received for the conduct of this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of KayseriTraining and Research Hospital\u0026nbsp;(Approval no:09.2016.359). Written informed consent was obtained from all patients included in the study in accordance with the ethical standards and the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e: The authors declare that they have no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eEstes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 2018; 67:123\u0026ndash;133. \u003c/li\u003e\n\u003cli\u003eHuang Y, Wang Y, Xiao Z, Yao S, Tang Y, Zhou L, et al. The association between metabolic dysfunction-associated steatotic liver disease, cardiovascular and cerebrovascular diseases and the thickness of carotid plaque. BMC Cardiovasc Disord 2023; 23(1): 554.\u003c/li\u003e\n\u003cli\u003eOzel Coskun BD, Yucesoy M, Gursoy S, Baskol M, Yurci A, Yagbasan A, et al. Effects of ursodeoxycholic acid therapy on carotid intima media thickness, apolipoprotein A1, apolipoprotein B, and apolipoprotein B/A1 ratio in nonalcoholic steatohepatitis. Eur J Gastroenterol Hepatol 2015; 27 (2): 142-9.\u003c/li\u003e\n\u003cli\u003eMladenova IL, Tam EF., Ng JY, Sharma P. Non-alcoholic fatty liver disease (NAFLD) and its association to cardiovascular disease: A comprehensive meta-analysis. JRSM Cardiovasc Dis 2025; 14:20480040251325929. \u003c/li\u003e\n\u003cli\u003eCano-Contreras AD, Francisco MDR, Vargas-Basurto JL, Gonz\u0026aacute;lez-G\u0026oacute;mez KD, Vivanco-Cid H, Hern\u0026aacute;ndez-Flores KG, et al. Hepatokine and Proinflammatory Cytokine Profile in Patients with Carotid Atherosclerosis and Metabolic Dysfunction-Associated Steatotic Liver Disease. Biomedicines 2025; 13(4):978.\u003c/li\u003e\n\u003cli\u003eCzerwińska M, Czarzasta K, Cudnoch-Jędrzejewska A. New Peptides as Potential Players in the Crosstalk Between the Brain and Obesity, Metabolic and Cardiovascular Diseases. Front Physiol 2021; 12:692642.\u003c/li\u003e\n\u003cli\u003eChang JB, Chu NF, Lin FH, Hsu JT, Chen PY. Relationship between plasma adropin levels and body composition and lipid characteristics amongst young adolescents in Taiwan. Obes Res Clin Pract 2018, 12 (1 Suppl 2): 101\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eKutlu O, Altun \u0026Ouml;, Dikker O, Aktaş Ş, \u0026Ouml;zsoy N, Arman Y, et al. Serum Adropin Levels Are Reduced in Adult Patients with Nonalcoholic Fatty Liver Disease. Med Princ Pract 2019; 28(5):463-469.\u003c/li\u003e\n\u003cli\u003eChen X, Sun X, Shen T, Chen Q, Chen S, Pang J, et al. Lower adropin expression is associated with oxidative stress and severity of nonalcoholic fatty liver disease. Free Radic Biol Med 2020; 160:191-198.\u003c/li\u003e\n\u003cli\u003eZhao LP, Xu WT, Wang L, You T, Chan SP, Zhao X, et al. Serum adropin level in patients with stable coronary artery disease. Heart Lung Circ 2015; 24(10): 975-9.\u003c/li\u003e\n\u003cli\u003eAltamimi TR, Gao S, Karwi QG, Fukushima A, Rawat S, Wagg CS, et al. Adropin regulates cardiac energy metabolism and improves cardiac function and efficiency. Metabolism 2019; 98: 37-48.\u003c/li\u003e\n\u003cli\u003eAydin S. Three new players in energy regulation: preptin, adropin and irisin. Peptides 2014; 56: 94-110. \u003c/li\u003e\n\u003cli\u003eCai H, Liu Q, Dong X, Cai Y, Yao J, Liu Y. Plasma preptin levels are decreased in patients with essential hypertension. Pharmazie 2018; 73 (5): 274-278. \u003c/li\u003e\n\u003cli\u003eMatthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28:412\u0026ndash;419.\u003c/li\u003e\n\u003cli\u003eTeng ML, Ng CH, Huang DQ, Chan KE, Tan DJ, Lim WH, et al. Global incidence and prevalence of nonalcoholic fatty liver disease. Clin Mol Hepatol 2023; 29(Suppl): S32-S42.\u003c/li\u003e\n\u003cli\u003eQuek J, Chan KE, Wong ZY, Tan C, Tan B, Lim WH, et al. Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. Lancet Gastroenterol Hepato 2023; 8(1): 20-30.\u003c/li\u003e\n\u003cli\u003eZhou Y, Duan S, Wang R, Chen J, Yao S. Nonlinear correlation between fatty liver index and carotid intima media thickness among individuals undergoing health examination. Front Endocrinol (Lausanne) 2023; 14:1120581. \u003c/li\u003e\n\u003cli\u003eGill C, Vatcheva KP, Pan JJ, Smulevitz B, McPherson DD, Fallon M, et al. Frequency of Nonalcoholic Fatty Liver Disease and Subclinical Atherosclerosis Among Young Mexican Americans. Am J Cardiol 2017; 119(11):1717-1722.\u003c/li\u003e\n\u003cli\u003eYang G, Li L, Chen W, Liu H, Boden G, Li K. Circulating preptin levels in normal, impaired glucose tolerance, and type 2 diabetic subjects. Ann Med 2009;41:52\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eKalaycı M, Halifeoğlu I, Kalaycı H, Uğur K, Yılmaz M. Plasma preptin levels in patients with type 2 diabetes mellitus. Int J Med Biochem 2019; 2(1):1-5\u003c/li\u003e\n\u003cli\u003eEl-Eshmawy M, Abdel Aal I. Relationships between preptin and osteocalcin in obese, overweight, and normal weight adults. Appl Physiol Nutr Metab 2015; 40 (3): 218-22.\u003c/li\u003e\n\u003cli\u003eArgun D, Basim P, Uysal BP, Argun F. Association of circulating preptin with non-alcoholic fatty liver disease: A case-control study. J Surg Med 2021;5(6):628-632.\u003c/li\u003e\n\u003cli\u003eJinJun W, QinQin W, XinYan L, YingMei L, WuJun X. Association between serum preptin level and insulin resistance in patients with nonalcoholic fatty liver disease. J Clin Hepatol 2016; 32 (9): 1774-1777.\u003c/li\u003e\n\u003cli\u003eWang H, Wang X, Cao Y, Han W, Guo Y, Yang G, et al. Association of polymorphisms of preptin, irisin and adropin genes with susceptibility to coronary artery disease and hypertension. Medicine (Baltimore) 2020; 99 (10): e19365. 27\u003c/li\u003e\n\u003cli\u003eLi B, Li Y, Zhang T, Song L, Lei C, Zhao Y, et al. Preptin is a new predictor of coronary artery calcification. Clin Chim Acta 2018; 485:133-138. \u003c/li\u003e\n\u003cli\u003eYassen ST, Farhan LO. Evaluation of Preptin and other Biomarkers in Coronary Artery Disease Patients with and without Diabetes Mellitus. J Fac Med Baghdad 2024; 66(4):431\u0026ndash;436.\u003c/li\u003e\n\u003cli\u003eAltamimi TR, Gao S, Karwi QG, Fukushima A, Rawat S, Wagg CS, et al. Adropin regulates cardiac energy metabolism and improves cardiac function and efficiency. Metabolism 2019; 98: 37-48.\u003c/li\u003e\n\u003cli\u003eZhao L‑P, You T, Chan S‑P, Chen J‑C, Xu W‑T. Adropin is associated with hyperhomocysteine and coronary atherosclerosis. Exp Ther Med. 2016;11(3): 1065\u0026ndash;1070.\u003c/li\u003e\n\u003cli\u003eWei W, Liu H, Qiu X, Zhang J, Huang J, Chen H, et al. The association between serum adropin and carotid atherosclerosis in patients with type 2 diabetes mellitus: a cross‑sectional study. Diabetol Metab Syndr 2022; 14(1): 27.\u003c/li\u003e\n\u003cli\u003eWu L, Fang J, Chen L, Zhao Z, Luo Y, Lin C, et al. Low serum adropin is associated with coronary atherosclerosis in type 2 diabetic and non-diabetic patients. Clin Chem Lab Med. 2014; 52 (5): 751-8.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Non-alcholic steatohepatitis, adropin, preptin, CIMT8","lastPublishedDoi":"10.21203/rs.3.rs-7279629/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7279629/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAdropin and preptin are recently identified as peptide hormones that act as potential mediators between metabolic dysfunction and vascular injury. However, their clinical relevance in non-alcoholic steatohepatitis (NASH) remains unclear. Thus, we aimed to evaluate serum adropin and preptin levels and their association with carotid intima-media thickness (CIMT) in patients with biopsy-proven NASH.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis cross-sectional study included 40 patients with histologically proven NASH and 30 age- and sex-matched healthy controls. This study enrolled 40 NASH patients and 30 healthy controls. None of the participants had diabetes, hypertension, or hyperlipidemia. Anthropometric, biochemical measurements and doppler ultrasonography were performed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eSerum adropin and preptin levels were significantly lower in NASH patients compared to controls (p\u0026thinsp;=\u0026thinsp;0.02 and p\u0026thinsp;=\u0026thinsp;0.03, respectively). Adropin levels were significantly negatively correlated with body mass index (BMI), body fat mass (BFM), body fat percentage (BFP), and HOMA-IR (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). In contrast, preptin levels showed no significant correlation with BMI, BFM, or BFP, and demonstrated a non-significant positive association with HOMA-IR. CIMT was significantly higher in NASH patients (0.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09 mm vs. 0.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06 mm; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and positively correlated with BMI and LDL, but not with adropin, preptin, or HOMA-IR. Furthermore, both peptides exhibited moderate negative correlations with steatosis grade and necroinflammatory activity (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), but they showed weak, non-significant negative correlations with fibrosis (p\u0026thinsp;=\u0026thinsp;0.08). In multivariate analysis, only BMI was independently associated with NASH (OR\u0026thinsp;=\u0026thinsp;1.44, 95% CI: 1.13\u0026ndash;1.84, p\u0026thinsp;=\u0026thinsp;0.004).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eReduced adropin and preptin levels in NASH patients were associated with metabolic and histological severity, independent of vascular changes. These peptides may serve as potential biomarkers for disease activity in NASH. But, further studies are needed to their clinical utility as biomarkers or therapeutic targets in NASH.\u003c/p\u003e","manuscriptTitle":"Circulating Adropin and Preptin In Non-Alcoholic Steatohepatitis and Their Relationship with Carotid Intima Media Thickness","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-08 14:34:07","doi":"10.21203/rs.3.rs-7279629/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-18T20:08:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-01T20:38:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"52967171583086047229937895425382790780","date":"2025-09-22T16:57:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-07T09:07:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"164514571764259885105949258289743762293","date":"2025-09-04T17:36:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"38734915686780621881869322737946885209","date":"2025-09-04T17:35:42+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-02T17:29:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-06T05:19:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-04T10:33:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Medical Research","date":"2025-08-02T17:01:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"346cd288-8b1b-48f1-a1b0-a96f042e5f68","owner":[],"postedDate":"September 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2025-11-18T20:23:08+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-08 14:34:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7279629","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7279629","identity":"rs-7279629","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}