No association between the functional cannabinoid receptor type 2 Q63R variants and inflammatory bowel disease in Turkish subjects.

BACKGROUND/AIMS: The endocannabinoid system can exert beneficial effects on gastrointestinal inflammation, and cannabinoid receptor-2 (CB2) agonists may represent a new therapeutic approach in inflammatory bowel disease (IBD). A functional CB2 Q63R polymorphism (rs35761398) in the CNR2 gene has been shown to affect the immunomodulating properties of the CB2 receptor. We sought to investigate whether the functional CB2 Q63R polymorphism (rs35761398) is associated with IBD susceptibility in a Turkish clinical sample. MATERIALS AND METHODS: A total of 202 IBD patients, comprising 101 Crohn's disease (CD) patients and 101 ulcerative colitis (UC) patients, and 101 healthy controls were included in the study. The CB2 Q63R polymorphism was genotyped using real-time PCR. RESULTS: There were no significant differences in the genotype frequencies of the three study groups. The odds ratio of the minor Q allele for CD relative to the common R allele was not significant (OR =1.02, 95% CI =0.67-1.56, p=0.99). Similarly, the odds ratio of the minor Q allele for UC relative to the common R allele did not reach statistical significance (OR =1.10, 95% CI =0.72-1.68, p=0.75). Moreover, the genotype frequencies did not show any significant association with the disease extent in either CD (p= 0.71) or UC patients (p=0.59). CONCLUSION: These pilot findings suggest that CB2 Q63R polymorphism does not play a major role in genetic susceptibility to IBD or in its disease phenotypes among Turkish subjects.

Primary malignant melanoma of the esophagus.

Primary malignant melanoma of the esophagus (PMME) comprises only 0.1-0.2% of all malignant esophageal tumors. PMME tumors are highly aggressive and metastasize early via hematogenic and lymphatic pathways. Treatment outcome is poor because the cancer has often advanced at the time of diagnosis. Inoperability, unsuccessful treatment with radiotherapy and chemotherapy in advanced tumors and metastases have contributed to its poor prognosis. Here, we present the endoscopic features, endoscopic ultrasonography findings and management of a PMME case.

Effects of sitagliptin in diabetic patients with nonalcoholic steatohepatitis.

BACKGROUND & AIMS: Preliminary evidence suggests that inhibition of dipeptidyl peptidase (DPP)-IV preserves pancreatic beta cell function in patients with type 2 diabetes (T2D). However, its effects on liver histology in nonalcoholic steatohepatitis (NASH), hepatic complication of diabetes, have not yet been adequately explored. The present open-label, single-arm observational pilot study investigated the effects of one year of treatment with a dipeptidyl peptidase-IV inhibitor, sitagliptin, on liver histology, body mass index (BMI), and laboratory parameters in NASH patients with T2D. PATIENTS AND METHODS: Paired liver biopsies from 15 diabetic patients with NASH (7 males, 8 females; mean age: 49.7 +/- 8.1 years (range: 36-62)) before and after one year of therapy with sitagliptin 100 mg once daily were studied. Clinical and laboratory parameters were recorded. RESULTS: Treatment with sitagliptin resulted in a significant decrease in ballooning (P = 0.014) and NASH scores (P = 0.04), while the reduction in the steatosis score was of borderline statistical significance (P = 0.054). These effects were accompanied by a significant reduction in body mass index, AST, and ALT levels. CONCLUSION: Our study suggests that sitagliptin ameliorates liver enzymes and hepatocyte ballooning in NASH patients with T2D and may have therapeutic implications.

The impact of early percutaneous endoscopic gastrostomy placement on treatment completeness and nutritional status in locally advanced head and neck cancer patients receiving chemoradiotherapy.

To investigate the impact of early insertion of percutaneous endoscopic gastrostomy-tube on nutritional status and completeness of concurrent chemotherapy in locally advanced head and neck cancer patients treated with chemoradiotherapy. Twenty-three patients were enrolled into this prospective study. Gastrostomy-tube was inserted in patients before the initiation of chemoradiotherapy. There was not any significant change in nutritional parameters of patients that used their tube during treatment. Despite the grade 3 mucositis, the planned concurrent chemotherapy could be given in 70% of the patients. However, nine patients had weak compliance and their body weight (P = 0.01) and body mass index (P = 0.01) deteriorated in the first 4 weeks of chemoradiotherapy. The completeness of concurrent chemo-rate was 44% in these patients. Toxicity, requiring aggressive supportive care, may limit the chemotherapy part of curative concomitant chemoradiotherapy. By providing adequate enteral nutrition the insertion of gastrostomy-tube can increase the completeness rate of concurrent chemotherapy.

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 (ß = 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.

Noninvasive assessment of liver fibrosis with the aspartate transaminase to platelet ratio index (APRI): Usefulness in patients with chronic liver disease: APRI in chronic liver disease.

BACKGROUND: The aspartate aminotransferases (AST) to platelet ratio index (APRI) may serve as a noninvasive marker to assess liver fibrosis. OBJECTIVES: To assess the diagnostic ability of the APRI for prediction of fibrosis in patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC), and non-alcoholic fatty liver disease (NAFLD). PATIENTS AND METHODS: This retrospective study included 207 patients with CHB, 108 with CHC, and 140 patients with NAFLD. The APRI was calculated as (AST level/upper normal limit for AST)/platelet counts (109/L) × 100. The stage of liver fibrosis in patients with chronic viral hepatitis was graded using the METAVIR scale. The Kleiner system for grading fibrosis was used in patients with NAFLD. RESULTS: Bivariate correlation analyses showed that the APRI was significantly associated with fibrosis scores in patients with CHC (p = 0.2634, p = 0.0059) and NAFLD (p = 0.2273, p = 0.0069), but not in those with CHB (p = 0.1005, p = 0.1495). Receiver operating characteristic (ROC) curves were used for assessing the ability of the APRI as a predictor of the absence or presence of liver fibrosis (fibrosis score of 0 vs fibrosis scores of 1-4). In patients with CHC, the APRI showed a sensitivity of 72.7% and a specificity of 62.4% for detection of fibrosis (p<0.01). In the NAFLD group, the APRI showed a sensitivity of 60.0% and specificity of 73.3% for detection of fibrosis (p<0.01). In patients with CHB, the APRI showed a sensitivity of 55.0% and a specificity of 75.4% for fibrosis (p=NS). CONCLUSIONS: The APRI shows an acceptable accuracy for the assessment of liver fibrosis in patients with CHC and NAFLD, but not in those with CHB.

Serum galectin-3 levels in patients with nonalcoholic fatty liver disease.

OBJECTIVES: Galectin-3 might serve as a biomarker of human metabolic alterations. We measured serum levels of galectin-3 in patients with nonalcoholic fatty liver disease (NAFLD) and examined their association with clinical and histological phenotypes. DESIGN AND METHODS: Serum levels of galectin-3 were assayed in 71 patients with biopsy-proven NAFLD and 39 controls. RESULTS: Serum galectin-3 levels did not differ in patients with NAFLD (median 4.1 ng/mL; interquartile range: 1.5-5.5 ng/mL) compared with healthy controls (median 3.1 ng/mL; interquartile range: 0.8-7.5 ng/mL, P=0.93). Among patients with NAFLD, however, serum galectin-3 levels correlated significantly with BMI (r=0.267, P<0.05). This association persisted after adjustment for potential confounders (ß=0.30; t=2.11, P<0.05). CONCLUSIONS: Although galectin-3 was modestly associated with BMI, our results do not support the hypothesis that levels of this molecule are altered in patients with NAFLD.

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 (ß=-0.53, t=-3.7, P<0.001), serum vaspin levels (ß=-0.30, t=-2.5, P=0.014), and liver fibrosis (ß=-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.

Circulating levels of vascular endothelial growth factor A and its soluble receptor in patients with biopsy-proven nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Vascular endothelial growth factor A (VEGF) is a multifunctional cytokine affecting angiogenesis and vascular function. The biological activity of VEGF is modulated by its soluble receptor VEGFR-1 (sVEGFR-1). We explored the associations of VEGF and sVEGFR-1 concentrations with liver histology in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). METHODS: The study was comprised of 99 patients with NAFLD and 75 healthy controls. Serum VEGF and sVEGFR-1 concentrations were measured using commercially available enzyme-linked immunosorbent assays. RESULTS: Serum VEGF levels did not differ in patients with NAFLD (1882 ± 942 pg/mL) compared with healthy controls (1985 ± 945 pg/mL, p = 0.42). However, compared with healthy subjects, levels of sVEGFR-1 were significantly lower in patients with NAFLD (1.59 ± 0.58 ng/mL vs. 1.16 ± 0.34 ng/mL, respectively, p <0.001). After allowance for potential confounders, serum sVEGFR-1 levels retained their independent significance as a predictor of liver fibrosis in patients with NAFLD (ß = -0.19; t = -1.81, p <0.05). CONCLUSIONS: Our results show that patients with biopsy-proven NAFLD have a significant reduction in serum sVEGFR-1 concentrations that predict the degree of liver fibrosis, independent of potential confounders.

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

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 (ß = 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.

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 (ß = 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 zinc-α2-glycoprotein concentrations in patients with non-alcoholic fatty liver disease.

BACKGROUND: Evidence suggests that zinc-α(2)-glycoprotein (ZAG) might serve as a biomarker for human metabolic alterations. We measured serum ZAG in patients with non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, and examined its association with clinical, biochemical, and histological phenotypes. METHODS: Serum ZAG was determined using ELISA in 90 patients with biopsy-proven NAFLD and 81 controls. RESULTS: Serum ZAG concentrations did not differ in patients with NAFLD (median 61 µg/mL; interquartile range: 56-73 µg/mL) compared with healthy controls (median 66 µg/mL; interquartile range: 56-78 µg/mL, Mann-Whitney U-test, p=NS). However, among patients with NAFLD serum ZAG concentrations were significantly higher in males and in those with the metabolic syndrome. After stepwise linear regression analysis, serum ZAG concentrations were the only independent predictor of the number of metabolic syndrome components in patients with NAFLD (ß=0.22; t=2.001, p<0.05). CONCLUSIONS: In summary, the hypothesis of an association between NAFLD and serum ZAG concentrations is not supported by the present results. However, ZAG remains an interesting molecule for further research in the field of human metabolic disorders.

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

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 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, Student's t test, P < 0.001). Bivariate analyses (Spearman's 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.

Caspase-cleaved fragments of cytokeratin 18 in patients with chronic hepatitis B.

BACKGROUND: During hepatocyte apoptosis, intermediate filament protein cytokeratin 18 is cleaved by caspases at Asp396 which can be specifically detected by the monoclonal antibody M30 (M30-antigen). In this study, we sought to determine whether serum M30-antigen levels can serve as a useful biomarker of liver injury in the clinical spectrum of HBV infection. METHODS: Serum M30-antigen levels were measured in inactive HBV carriers (n=54), patients with HBeAg-negative chronic hepatitis B (CHB, n=47), patients with HBeAg-positive CHB (n=42) and healthy controls (n=29). All subjects were treatment-naïve. RESULTS: There were significant differences in serum M30-antigen levels across the study groups (P<0.001; Kruskal-Wallis test). Post hoc analyses revealed that M30-antigen levels did not differ significantly between inactive HBV carriers (median 109.6 U/L) and healthy controls (median 106.1 U/L). However, both patients with HBeAg-negative (CHB, median 182.9 U/L, P<0.001) and HBeAg-positive CHB (median 158.3 U/L, P<0.001) had significantly higher levels of M30-antigen compared with inactive HBV carriers. CONCLUSIONS: Hepatocyte apoptotic activity--as reflected by serum M30-antigen levels--is increased in chronic active hepatitis B, but is not associated with the HBeAg status. In contrast, apoptosis does not appear to be a prominent feature of inactive HBV carriers.

Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease.

BACKGROUND: The fibroblast growth factor 21 (FGF21) hormonal pathway is a metabolic signalling cascade and has been recently identified as the master hormonal regulator of glucose, lipids and overall energy balance. In this observational, case-control study, we assayed serum levels of FGF21 in patients with nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, and examined their association with clinical, biochemical and histological phenotypes. MATERIALS AND METHODS: Serum levels of FGF21 were assayed by ELISA in 82 patients with biopsy-proven NAFLD and 77 controls. We analysed associations between FGF21 and the characteristics of patients with NAFLD by multiple linear regression analysis. RESULTS: Levels of FGF21 were significantly higher in patients with NAFLD (median 200 pg mL(-1) ; interquartile range: 87-410 pg mL(-1)) than in healthy controls (median 93 pg mL(-1) ; interquartile range: 70-180 pg mL(-1) , Mann-Whitney U-test, P<0·001). There was a stepwise increase in serum FGF21 levels according to the liver steatosis score (median level in subjects with score 1: 170 pg mL(-1) ; score 2: 220 pg mL(-1) ; score 3: 280 pg mL(-1) , P for trend <0·01). After stepwise linear regression analysis, serum FGF21 levels were the only independent predictor of hepatic steatosis scores in patients with NAFLD (ß=0·26; t=2·659, P<0·01). CONCLUSIONS: Serum FGF21 levels are increased in patients with NAFLD regardless of potential confounders and represent an independent predictor of liver steatosis. These findings support further investigation of this molecule in metabolic liver diseases.