Ozlen Atug

Decreased plasma levels of soluble receptor for advanced glycation endproducts (sRAGE) in patients with nonalcoholic fatty liver disease

OBJECTIVES Levels of soluble receptor for advanced glycation endproducts (sRAGE) have been linked to several components of the metabolic syndrome. We tested the hypothesis that plasma levels of sRAGE may be associated with non-alcoholic fatty liver disease. DESIGN AND METHODS We enrolled subjects with definite nonalcoholic steatohepatitis (NASH, n=40), borderline NASH (n=8), simple fatty liver (n=9) and healthy controls (n=14). Plasma levels of sRAGE were measured by ELISA. RESULTS Concentrations of sRAGE were significantly lower in patients with definite NASH (1080+/-392 pg/mL, P<0.01) and borderline NASH (1050+/-278 pg/mL, P<0.05) compared to controls (1480+/-387 pg/mL). Levels of sRAGE were significantly and inversely correlated with ALT (r=-0.30, P<0.05) and AST (r=-0.23, P<0.05). CONCLUSION Plasma levels of sRAGE are significantly reduced in definite and borderline NASH.

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.

Clinical characteristics of inflammatory bowel disease in Turkey: a multicenter epidemiologic survey.

Aim To investigate the epidemiologic and clinical characteristics of inflammatory bowel disease (IBD) patients in a large multicenter, countrywide, hospital-based study in Turkey. Materials and Methods Twelve centers uniformly distributed throughout Turkey reported through a questionnaire the new IBD cases between 2001 and 2003. The incidence of ulcerative colitis (UC) and Crohns disease (CD) has been reported per 100,000 people. Epidemiologic features and clinical characteristics of both diseases were analyzed. Results During the study period, 661 patients of UC and 216 patients of CD were identified. The incidence in the referral population was 4.4/100,000 and 2.2/100,000 for UC and CD, respectively. The age of the patients showed the characteristic biphasic distribution with 2 peaks between 20 and 30 and 50 and 70 years. A male predominance was observed in both diseases. A history of smoking was detected in 15.5% of UC patients and 49.3% of patients with CD. Family history was positive in 4.4% in UC and 8.3% in CD patients. Concomitant amebiasis was observed in 17.3% of patients with UC and 1.3% of patients with CD. A history of appendectomy was reported in 15% of patients with CD and only 3% of patients with UC. Both extraintestinal and local complications were more frequent in CD patients, whereas arthritis was most common in both diseases. Conclusions IBDs are frequently encountered in Turkey. IBD incidence is lower than North and West Europe but close to Middle East in our country. The majority of IBD cases are diagnosed in young people (20 to 40 y) with predominance in males. The rate of both intestinal and extraintestinal complications in our population was low when compared with the data reported in the literature. IBD and especially UC, can coexist with amebiasis or become manifest with amebic infestation. The presence of concomitant ameba may create confusion and cause dilemmas in the diagnosis and treatment of UC.

Preliminary evidence of a reduced serum level of fibroblast growth factor 19 in patients with biopsy-proven nonalcoholic fatty liver disease.

OBJECTIVES We sought to determine whether serum concentrations of fibroblast growth factor 19 (FGF19) - an ileum-derived enterokine which plays a role in the control of glucose and lipid homeostasis - are altered in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). DESIGN AND METHODS Serum levels of FGF19 were measured using enzyme-linked immunosorbent assay in 91 patients with biopsy-proven NAFLD and 74 controls. RESULTS FGF19 levels were significantly lower in patients with biopsy-proven NAFLD (median: 130pg/mL) than in controls (median: 210pg/mL, P<0.001). Serum FGF19 levels were significantly but modestly associated with hepatocyte ballooning scores in univariate analysis (r=-0.25, P<0.05) but not after adjustment for potential confounders (β=-0.18; t=1.78, P=0.08). CONCLUSIONS This pilot study suggests that serum FGF19 levels are decreased in patients with NAFLD but are not independently associated with liver histology findings.

Serum levels of adipokines in patients with chronic HCV infection: relationship with steatosis and fibrosis.

BACKGROUND AND AIMS Hepatic steatosis and fibrosis are common histological findings in patients with chronic hepatitis C virus (HCV) infection. In this study we sought to determine whether serum levels of three adipokines (leptin, adiponectin and resistin) show any biochemical correlation with hepatic steatosis and fibrosis in patients with chronic HCV infection. METHODS We examined a total of 51 patients with chronic HCV infection (22 males and 29 females, mean BMI: 27.4+/-5kg/m(2)) and 24 healthy control subjects (10 males and 14 females, mean BMI: 23.2+/-3kg/m(2)). Liver steatosis and fibrosis were scored on biopsies. Serum levels of leptin, adiponectin and resistin were determined by ELISA. RESULTS HCV genotypes were 1b in 41 patients (80.4%), 3a in three patients (5.9%), 2a in two patients (3.9%), 1a in two patients (3.9%), 1c in one patient (2%), and 2b in one patient (2%). Serum levels of leptin, resistin, and the leptin-to-adiponectin ratio were significantly higher in patients with chronic HCV infection than in controls. Steatosis and fibrosis were detected in 33.3% and 70.5% of chronic HCV patients, respectively. No significant association with serum adipokine levels and degree of steatosis was evident. Low serum levels of resistin were associated with the presence of fibrosis independently of potential confounders. CONCLUSIONS Patients with chronic HCV infection display elevated levels of adipokines in their sera. Reduced concentrations of resistin may be a biochemical marker of fibrosis in this patient group.

Serum concentrations of human angiopoietin-like protein 3 in patients with nonalcoholic fatty liver disease: association with insulin resistance.

Objective Insulin resistance is considered a key feature of nonalcoholic fatty liver disease (NAFLD). In this setting, experimental studies have suggested a potential role of angiopoietin-like (ANGPTL) proteins in the pathogenesis of hepatic steatosis and the metabolic syndrome. In this study, we sought to investigate the plasma levels of ANGPTL protein 3 (ANGPTL3) – a liver-derived protein that modulates plasma triglyceride clearance – in patients with definite nonalcoholic steatohepatitis (NASH, n=40), borderline NASH (n=8), simple fatty liver (n=9), and healthy controls without evidence of liver disease (n=14). Methods Levels of ANGPTL3 were measured by enzyme-linked immunosorbent assay and compared in the four study groups. Moreover, concentrations of ANGPTL3 were assessed in relation to the general characteristics of the study participants and the results of liver biopsy. Results Levels of ANGPTL3 were significantly higher in patients with definite NASH (389±110 ng/ml, P<0.05) and borderline NASH (433±70 ng/ml, P<0.05) compared with controls (291±78 ng/ml). No significant differences were found in patients with simple fatty liver (321±119 ng/ml) as compared with controls. In correlation analyses of the entire study cohort, ANGPTL3 was significantly and positively associated with homeostatic model assessment for insulin resistance (r=0.28, P<0.05) but not with histological staging and pathological characteristics of NAFLD. Conclusion Although subject to future confirmation, our data suggest that ANGPTL3 levels are elevated in the more severe forms of NAFLD and could be associated with insulin resistance in this setting.

Critical pH level of lye (NaOH) for esophageal injury.

Aim/Background Lye (NaOH) ingestion in humans often results in alkaline damage to the esophagus, but knowledge about this process is limited. Here, we explore the effects of lye on esophageal epithelial structure and function using rabbit esophageal epithelium as a model of lye ingestion. Methods Rabbit esophageal epithelium was mounted in Ussing chambers so that the electrical potential difference (PD), short-circuit current (Isc), and transepithelial resistance (RT) could be monitored before, during, and after mucosal exposure to lye (NaOH) at pHs ranging from 7.4 to 12.1. Histopathology and dextran fluxes were also performed and correlated with the electrical data. Results Mucosal exposure to lye at pHs <11.5 had no damaging effects on the esophagus. However, at pHs ≥11.5, damage was both time- and pH-dependent, as noted by increases in PD and Isc, and declines in RT. Further, the electrical changes were paralleled morphologically by epithelial liquefaction necrosis and increases in dextran flux. Also, by pretreating tissues with ouabain, the early lye-induced rise in PD and Isc was shown to result from a combination of increased active (sodium) transport and passive (sodium) diffusion which indicates that, even early on, the damaging effects of lye include changes in both apical cell membranes and tight junctions of this epithelium. Conclusion Lye (NaOH) injury to the esophageal epithelium is both pH- and time-dependent, but requires a minimum pH of 11.5. At pHs ≥11.5, lye produces liquefaction necrosis, an injury that involves both cellular and junctional barriers, and which markedly increases epithelial permeability to ions and uncharged molecules. Based on these results, non-industrial cleaning products in the home are likely to be safer if they have a concentration of lye below pH 11.5.

The effects of psychiatric treatment on depression, anxiety, quality of life, and sexual dysfunction in patients with inflammatory bowel disease

Objective Depression and anxiety are common disorders in inflammatory bowel disease (IBD). Our aim is to prospectively determine the effect of psychiatric treatment on scores for depression, anxiety, quality of life (QoL), and sexual dysfunction in an outpatient population diagnosed with IBD and also anxiety and/or depression disorder. Patients and methods Patients who scored higher than the cutoff point on the Hospital Anxiety Depression Scale were referred for further structured psychiatric evaluation and determination of the need for psychiatric drug treatment. Patients who underwent drug therapy completed Short Form-36 (SF-36) and the Arizona Sexual Experience Scale at baseline and after 6 months of follow-up. Results Major depressive disorder and generalized anxiety disorder were the most common diagnoses. After 6 months, 47 patients had completely adhered to drug treatment (group A), whereas 20 were nonadherent (group B). In group A, all domains of SF-36, Arizona Sexual Experience Scale, depression/anxiety scores, and Crohn’s disease activity index were statistically improved after treatment when compared with the baseline. In group B, the three domains of SF-36, platelet count, and mean corpuscular volume were worse between baseline and at 6 months. Conclusion In IBD patients having any psychiatric disorder, 6 months of antidepressant drug treatment is associated with an improvement in depression, anxiety, QoL, and sexual functioning scores, as well as an improvement in Crohn’s disease activity index. On the other hand, insufficient psychiatric treatment seems to be related to a poor QoL.

Association between bactericidal/permeability increasing protein (BPI) gene polymorphism (Lys216Glu) and inflammatory bowel disease

BACKGROUND Increasing evidence suggests that innate immune system may have a key role in the pathogenesis of the inflammatory bowel disease (IBD). Bactericidal/permeability increasing protein (BPI) has an important role in the recognition and neutralization of gram-negative bacteria by host innate immune system. The polymorphism on BPI gene called Lys216Glu is on the suspected list of IBD pathogenesis. METHODS We studied the Lys216Glu polymorphism on BPI gene, in a Turkish IBD patient population. A total of 238 IBD patients; 116 Crohns disease (CD) and 122 ulcerative colitis (UC), besides 197 healthy controls were included in this study. RESULTS The Glu/Glu genotype and allele frequencies were found to be statistically higher compared to healthy control group not only in CD patients [P: 0.03, OR: 1.87 (CI 95% 1.02-3.42) and P: 0.00001 (OR: 2.07 CI 95% 1.47-2.91) respectively] but also in UC patients [P: 0.0002, OR: 2.71 (CI 95% 1.53-4.80) and P: 0.00002 (OR: 2.71 CI 95% 1.53-4.80) respectively]. CONCLUSIONS BPI polymorphism (Lys216Glu) is associated both to CD and UC. Our findings differ from the two Western European studies; one without any association and the other indicating an association only with CD. Our study is the first one reporting a novel association between BPI gene mutation (Lys216Glu) and UC.

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.