Oya Yonal

Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease

Eur J Clin Invest 2010; 40 (10): 887–892

Serum levels of omentin, chemerin and adipsin in patients with biopsy-proven nonalcoholic fatty liver disease

Abstract Objective. The novel adipokines omentin, chemerin, and adipsin are associated with insulin resistance and the components of the metabolic syndrome. We assayed circulating levels of these molecules and examined their association with clinical, biochemical, and histological phenotypes in patients with nonalcoholic fatty liver disease (NAFLD). Material and methods. Serum levels of omentin, chemerin, and adipsin were assayed by enzyme-linked immunosorbent assay in 99 patients with biopsy-proven NAFLD and 75 control subjects. We analyzed associations between adipokines and the characteristics of patients with NAFLD using multivariable linear regression models. Results. Adipsin levels did not differ between patients and controls, whereas both omentin and chemerin levels were significantly higher in patients with biopsy-proven NAFLD than in controls (both p values <0.001). Serum omentin levels were significantly associated with C-reactive protein (r = 0.29, p < 0.01) and the degree of hepatocyte ballooning (r = 0.27, p < 0.01), whereas chemerin showed a modest association with liver fibrosis (r = 0.22, p = 0.04). After stepwise linear regression analysis adjusting for potential confounders, serum omentin levels retained their independent significance as a predictor of hepatocyte ballooning in patients with NAFLD (β = 1.42; t = 2.79, p < 0.01). Conclusions. Our results suggest that serum omentin levels are raised in patients with NAFLD regardless of potential confounders and represent an independent predictor of hepatocyte ballooning.

Microalbuminuria in nondiabetic patients with nonalcoholic fatty liver disease: association with liver fibrosis.

Recent evidence has suggested an association between microalbuminuria and ultrasound-diagnosed nonalcoholic fatty liver disease (NAFLD) in patients with diabetes and prediabetes. However, few data are available on the occurrence of microalbuminuria in nondiabetic subjects with histologically proven NAFLD. We thus evaluated the relationships between microalbuminuria and liver histology in a hospital-based sample of 87 adults with biopsy-proven NAFLD from Turkey. An albumin excretion rate less than 30 mg/d was considered within the reference range, whereas an albumin excretion rate from 30 to 300 mg/d was considered to indicate microalbuminuria. Compared with those without microalbuminuria (n = 73), NAFLD patients with microalbuminuria (n = 14) had significantly higher homeostasis model assessment of insulin resistance values (3.9 +/- 1.3 vs 5.8 +/- 3.7, P < .001). There were no differences in the prevalence of microalbuminuria in patients with definite nonalcoholic steatohepatitis, borderline nonalcoholic steatohepatitis, and simple fatty liver. In the entire study cohort, mean fibrosis scores were significantly higher in patients with microalbuminuria than in those without (1.27 +/- 0.26 vs 0. 80 +/- 0.11, P < .05). This difference persisted after adjustment for potential confounders. These results indicate the presence of a significant association between the severity of insulin resistance and microalbuminuria in patients with NAFLD. In addition, microalbuminuria may identify NAFLD patients with higher fibrosis scores.

Coronary flow reserve is impaired in patients with nonalcoholic fatty liver disease: Association with liver fibrosis

BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease. Coronary flow reserve (CFR) is widely used to examine the integrity of coronary microvascular circulation. We evaluated the prevalence of impaired CFR in patients with biopsy-proven NAFLD. We also investigated the independent clinical, biochemical, and liver histology predictors of CFR in the setting of NAFLD. METHODS Fifty-nine consecutive patients with NAFLD and 77 age- and gender-matched controls were evaluated. CFR recordings were performed by transthoracic Doppler harmonic echocardiography. CFR>or=2.0 was considered normal. RESULTS CFR was significantly lower in patients with NAFLD than in controls (2.11+/-0.45 vs. 2.52+/-0.62, P<0.001). An impaired CFR (i.e. <2) was found in 25 NAFLD patients (42.4%) whereas all controls had normal CFR values (P<0.001). A stepwise linear regression analysis in NAFLD patients identified liver fibrosis scores as the only independent predictor of CFR values (beta=-0.60; t=-2.44, P=0.021). CONCLUSION Our findings indicate that in patients with biopsy-proven NAFLD: (a) an abnormal CFR is found in approximately 42.4% of cases, and (b) liver fibrosis scores are an independent predictor of depressed CFR.

Serum levels of vaspin, obestatin, and apelin-36 in patients with nonalcoholic fatty liver disease.

The novel adipokines vaspin, obestatin, and apelin-36 are associated with insulin resistance and the components of the metabolic syndrome. We assayed circulating levels of these molecules and examined their association with clinical, biochemical, and histologic phenotypes in patients with nonalcoholic fatty liver disease (NAFLD). Serum levels of vaspin, obestatin, and apelin-36 were assayed by enzyme-linked immunosorbent assay in 91 patients with biopsy-proven NAFLD and 81 controls. We analyzed associations between adipokines and the characteristics of patients with NAFLD using multivariable linear regression models. Univariable analysis showed that concentrations of vaspin and apelin-36 were significantly higher in patients with NAFLD than in controls, whereas no differences in obestatin levels were found. Serum vaspin levels showed a statistically significant association with C-reactive protein (r = 0.378, P < .001) and liver fibrosis scores (r = 0.401, P < .001), whereas apelin-36 levels showed a modest association with homeostasis model assessment of insulin resistance (r = 0.204, P < .01). After stepwise linear regression analysis, serum vaspin levels were the only independent predictor of liver fibrosis scores in patients with NAFLD (β = 0.37, t = 3.99, P < .01). Serum vaspin levels are raised in patients with NAFLD regardless of potential confounders and represent an independent predictor of liver fibrosis scores. These findings support further investigation of this novel adipokine in metabolic liver diseases.

Serum fetuin A/α2HS-glycoprotein levels in patients with non-alcoholic fatty liver disease: relation with liver fibrosis

Background Serum concentrations of fetuin A/α2HS-glycoprotein (AHSG) have been linked to human metabolic alterations and can serve as an indicator of liver cell function. We assayed serum levels of AHSG in patients with non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, and examined their association with clinical, biochemical and histological phenotypes. Methods Serum AHSG levels were determined by enzyme linked immunosorbent assay in 99 patients with biopsy-proven NAFLD and 75 age- and gender-matched controls. Results Serum AHSG levels were significantly higher in patients with NAFLD (940 ± 120 μg/mL) compared with healthy controls (800 ± 130 μg/mL, Students t test, P < 0.001). Bivariate analyses (Spearmans rank correlation) in patients with NAFLD showed a statistically significant association between AHSG levels and insulin resistance as assessed by the HOMA (homeostasis model assessment) index (r = 0.31, P < 0.01) and the liver fibrosis score index (r = 0.36, P < 0.001). The association between AHSG and fibrosis remained statistically significant even after adjustment for potential confounders, including the HOMA index ([beta] = 1.65, t = 2.38, P < 0.05). Conclusion Serum AHSG levels are significantly increased in adult patients with biopsy-proven NAFLD and are associated with insulin resistance. Importantly, our pilot data indicate that serum AHSG levels may identify NAFLD patients with higher fibrosis scores.

Circulating vaspin levels and epicardial adipose tissue thickness are associated with impaired coronary flow reserve in patients with nonalcoholic fatty liver disease

BACKGROUND Patients with nonalcoholic fatty liver disease (NAFLD) have a reduced coronary flow reserve (CFR) and an increased risk of cardiovascular disease. The fat cells that surround coronary arteries may play a central and underrecognized role in development of cardiovascular disease through the systemic secretion of adipokines. We therefore evaluated the relation of epicardial fat thickness, serum levels of epicardial fat-related adipokines (chemerin and vaspin), and CFR in patients with NAFLD. METHODS We investigated 54 patients with biopsy-proven NAFLD and 56 age- and sex-matched controls. CFR and epicardial fat thickness (EFT) were measured by transthoracic echocardiography. Serum levels of chemerin and vaspin were measured by ELISA. RESULTS EFT was significantly higher (0.64 ± 0.13 vs. 0.54 ± 0.10 cm, P<0.001) and CFR significantly lower (2.11 ± 0.45 vs. 2.52 ± 0.62, P < 0.001) in patients with NAFLD than in controls. Serum levels of vaspin and chemerin were both significantly increased in patients with NAFLD compared with controls. Stepwise regression analysis showed that EFT (β=-0.53, t=-3.7, P<0.001), serum vaspin levels (β=-0.30, t=-2.5, P=0.014), and liver fibrosis (β=-0.31, t=-2.11, P=0.041), in the order they entered into the model, were independent predictors of CFR in NAFLD patients. CONCLUSION Our data suggest the presence of a complex interplay between EFT, serum vaspin, and liver histology in promoting an impaired hyperemic stimulation of coronary blood flow in patients with NAFLD.

Serum progranulin as an independent marker of liver fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease

Background: Elevated progranulin levels are associated with visceral obesity, elevated plasma glucose, and dyslipidemia. Progranulin has not been previously investigated as a biomarker of nonalcoholic fatty liver disease (NAFLD). We sought to determine whether serum progranulin levels are altered in patients with biopsy-proven NAFLD and if they are associated with their clinical, biochemical, and histological characteristics. Subjects and methods: We measured serum progranulin levels in 95 patients with biopsy-proven NAFLD and 80 age- and sex-matched controls. The potential associations between progranulin and the characteristics of NAFLD patients were examined by multiple linear regression analysis. Results: Serum progranulin levels were significantly higher in NAFLD patients (34 ± 13 ng/mL) than in controls (28 ± 7 ng/mL, P < 0.001). In NAFLD patients, serum progranulin levels were associated with lipid levels and the degree of hepatic fibrosis. After adjustment for potential confounders, serum progranulin remained an independent predictor of the degree of hepatic fibrosis in NAFLD patients (β = 0.392; t =2.226, P < 0.01). Conclusions: Compared with controls, NAFLD patients have higher serum progranulin concentrations, which are closely associated with lipid values and the extent of hepatic fibrosis.

Serum levels of osteoprotegerin in the spectrum of nonalcoholic fatty liver disease

Abstract Objective. Osteoprotegerin (OPG) is a member of the tumor necrosis factor superfamily with pleiotropic effects on inflammation, endocrine function and the immune system. Reduced OPG levels are related to insulin resistance. We tested the hypothesis that serum levels of OPG may be associated with nonalcoholic fatty liver disease (NAFLD). Material and methods. Four groups of patients were enrolled in the present study: subjects with definite nonalcoholic steatohepatitis (NASH, n = 56), borderline NASH (n = 26), simple fatty liver (n = 17) and healthy controls without evidence of liver disease (n = 58). Serum levels of OPG were measured by ELISA. Results. Concentrations of OPG were significantly lower in patients with definite NASH (median: 45 pg/mL, p < 0.001) and borderline NASH (57 pg/mL, p < 0.001) than in controls (92 pg/mL). The area under the ROC curve for distinguishing between steatohepatitis (definite NASH plus borderline NASH) and healthy controls using OPG was 0.82. The use of a cut-off level < 74 pg/mL for serum OPG levels yielded sensitivity and specificity values of 75.6% and 75.9%, respectively. Conclusions. Serum osteoprotegerin concentrations are reduced in patients with the more severe forms of NAFLD and may serve as a noninvasive biomarker to identify patients with NASH.

Serum levels of soluble receptor for advanced glycation endproducts (sRAGE) are higher in ulcerative colitis and correlate with disease activity

UNLABELLED Interaction of the receptor for advanced glycation endproducts (RAGE) with its ligands results in expression of inflammatory mediators, activation of NF-κB, and induction of oxidative stress, all of which have been implicated in the pathogenesis of inflammatory bowel diseases (IBD). Soluble receptor for advanced glycation endproducts (sRAGE) has recently emerged as a reliable biomarker of inflammation in numerous RAGE-mediated disorders. OBJECTIVE To assess sRAGE levels in adult patients with IBD. METHOD Serum was collected from adult patients with Crohns disease (CD, 56 patients), ulcerative colitis (UC, 60 patients), and healthy controls (HC, 113 subjects). Levels of sRAGE were determined by enzyme-linked immunosorbent assay. RESULTS Serum sRAGE levels were elevated in IBD compared to HC and were higher in UC patients compared to CD and HC. Levels of sRAGE were significantly higher in the serum of UC patients with active disease compared to patients with inactive disease, but no association with the Montreal Classification was evident. Serum sRAGE was lower in CD patients with biological therapies. CONCLUSIONS These findings suggest that serum levels of sRAGE are altered in patients with intestinal inflammation and may reflect distinct immunoinflammatory pathogenesis of UC and CD.