Erol Avsar

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.

Prevalence of Hepatic Granulomas in Chronic Hepatitis B

An increasing frequency of hepatic granulomas, up to 10%, in chronic hepatitis C patients is reported, and their presence is considered to be a predictor of treatment success. However, there is only one prevalence study on granuloma in chronic hepatitis B, and its significance for treatment outcome is unknown. We aimed to determine the prevalence of hepatic granulomas in a larger group of chronic hepatitis B patients and to compare their presence with the response to interferon therapy. Biopsy specimens of chronic hepatitis B patients were reevaluated for the presence of hepatic granulomas. All patients with hepatic granuloma were screened for other granulomatous diseases by tuberculin skin test, chest X-ray and computed tomography, venereal disease research laboratory, Brucella agglutination tests, and exposure to hepatotoxic agents. We screened 663 cases of chronic hepatitis B. Hepatic granulomas were found in 10 cases (1.5%). The granulomas could not be ascribed to any other reason. Of the 10 patients with hepatic granulomas, 4 responded to interferon therapy, 2 dropped out, and 4 were nonresponders. We conclude that hepatic granuloma is a rare finding in chronic hepatitis B and its presence does not seem to predict the response to interferon therapy.

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.

Melatonin ameliorates methionine- and choline-deficient diet-induced nonalcoholic steatohepatitis in rats.

Abstract:  Nonalcoholic steatohepatitis (NASH) may progress to advanced fibrosis and cirrhosis. Mainly, oxidative stress and excessive hepatocyte apoptosis are implicated in the pathogenesis of progressive NASH. Melatonin is not only a powerful antioxidant but also an anti‐inflammatory and anti‐apoptotic agent. We aimed to evaluate the effects of melatonin on methionine‐ and choline‐deficient diet (MCDD)‐induced NASH in rats. Thirty‐two male Wistar rats were divided into four groups. Two groups were fed with MCDD while the other two groups were fed a control diet, pair‐fed. One of the MCDD groups and one of the control diet groups were administered melatonin 50 mg/kg/day intraperitoneally, and the controls were given a vehicle. After 1 month the liver tissue oxidative stress markers, proinflammatory cytokines and hepatocyte apoptosis were studied by commercially available kits. For grading and staging histological lesions, Brunt et al.’s system was used. Melatonin decreased oxidative stress, proinflammatory cytokines and hepatocyte apoptosis. The drug ameliorated the grade of NASH. The present study suggests that melatonin functions as a potent antioxidant, anti‐inflammatory and antiapoptotic agent in NASH and may be a therapeutic option.

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.