Osman Ozdogan

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.

Causes and risk factors for liver injury following bone marrow transplantation.

Goals: A retrospective study of pretransplantation risk factors predisposing to liver injury following bone marrow transplantation (BMT). Background: Liver complications are a major cause of morbidity and mortality following BMT. Determination of the pretransplantation factors that are likely to lead to liver injury may allow earlier diagnosis after BMT and may possibly improve prognosis. Study: Medical records of BMT patients were reviewed, and results of serial liver function tests and HBV/HCV serology during the pre‐ and posttransplantation 1‐year period were noted. Presence of liver injury was defined as alanine aminotransferase levels twice the upper limit of normal. Forty‐four allogeneic and 17 autologous BMTs, performed between 1990 and 2000, were analyzed in the study. Results and Conclusion: One‐year survival was 77% (34 of 44 patients) for allogeneic BMT and 52% (9 of 17 patients) for autologous BMT. Seventy‐two percent (32 of 44) of allogeneic transplant recipients and 47% (8 of 17) of autologous transplant recipients had liver injury during the first year of BMT. The most frequent causes of liver injury were graft‐versus‐host disease and drug hepatotoxicity for allogeneic BMT and drug hepatotoxicity for autologous BMT. Fulminant hepatic failure occurred in one allogeneic transplant recipient who was a pretrans‐plantation HBV carrier and led to death. Multivariate regression analysis showed that pretransplantation HBV/HCV positivity and pretransplantation elevated liver enzyme levels of any cause were predictive risk factors for post‐BMT liver injury, and close follow‐up, early diagnosis, and treatment are highly recommended for BMT patients with these risk factors.

In vivo inefficiency of pentoxifylline and interferon-alpha on hepatic fibrosis in biliary-obstructed rats: Assessment by tissue collagen content and prolidase activity

Background and Aim: To evaluate the possible antifibrotic effects of two drugs, pentoxifylline (PTX) and interferon (IFN)‐α as well as their combination, on a bile‐duct‐ligated rat hepatic fibrosis model.