Effects of pioglitazone and metformin on abdominal adhesion formation in an experimental model.

BACKGROUND: This study evaluated the use of metformin or pioglitazone in preventing or reducing the development of post-operative intra-abdominal adhesion (PIAA) by employing histopathological, immunohistochemical, and biochemical analyses in an experimental adhesion model. METHODS: Fifty Wistar-Albino rats were divided into five groups: Group I (Control), Group II (Sham Treatment), Group III (Hy-aluronic Acid), Group IV (Metformin), and Group V (Pioglitazone). Adhesions were induced in the experimental groups, except for the sham group, using the scraping method. After 10 days, rats were euthanized for evaluation. Macroscopic adhesion degrees were assessed using Nair's scoring system. Immunohistochemical and enzyme-linked immunosorbent assay (ELISA) methods were utilized to assess serum, peritoneal lavage, and intestinal tissue samples. Fructosamine, interleukin-6 (IL-6), transforming growth factor-beta (TGF-ß), and fibronectin levels were measured in serum and peritoneal lavage samples. RESULTS: The groups exhibited similar Nair scores and Type I or Type III Collagen staining scores (all, p>0.05). Pioglitazone significantly reduced serum IL-6 and TGF-ß levels compared to controls (p=0.002 and p=0.008, respectively). Both metformin and pioglitazone groups showed elevated IL-6 in peritoneal lavage relative to controls, while fibronectin levels in the lavage were lower in pioglitazone-treated rats compared to the sham group (all, p<0.005). CONCLUSION: Pioglitazone, but not metformin, demonstrated a positive biochemical impact on preventing PIAA formation in an experimental rat model, although histological impacts were not observed. Further experimental studies employing different dose/duration regimens of pioglitazone are needed to enhance our understanding of its effect on PIAA formation.

Comparison of stent and indomethacin suppository efficacy in the prevention of acute pancreatitis after ERCP.

OBJECTIVE: We aimed to compare stent and indomethacin suppository efficacy in the prevention of acute pancreatitis after ERCP. MATERIALS AND METHODS: 76 high-risk patients undergoing ERCP were included in the study. The patients were divided into three groups as indomethacin group, stent group and control group. Indomethacin group (n = 32) received 100 mg rectal indomethacin immediately after ERCP. A 5F pancreatic stent was applied to the stent group (n = 16) during ERCP. No prophylaxis was given to the control group (n = 28). RESULTS: There was no difference between the groups in terms of age and gender. ERCP pancreatitis was seen in 9.2% (7/76) of the patients. The incidence of ERCP-induced pancreatitis (PEP) was 3.1% (1/32) in the indomethacin group and 21.4% (6/28) in the control group. PEP was not seen in the stent group (0/16). The incidence of PEP was significantly lower in the indomethacin group than in the control group (p = 0.043). However, no significant difference was found between the stent and control groups, stent and indomethacin groups in terms of PEP frequency (p = 0.072, p: 0.90 respectively). CONCLUSION: According to the results of our study, rectal indomethacin administration decreased the frequency of PEP in high-risk patients. However, there was no significant difference in PEP prophylaxis between the stent and indomethacin groups.

Inflammatory markers C-reactive protein and PLR in relation to HCC characteristics.

INTRODUCTION: Several markers of systemic inflammation, including blood C-reactive protein, platelet lymphocyte ratio (PLR) and neutrophil lymphocyte ratio (NLR) have been identified as independent prognosticators for hepatocellular carcinoma (HCC). METHODS: To attempt to understand the significance of these markers, they were examined in relation to 4 tumour parameters, namely maximum tumour diameter (MTD), tumour multifocality, portal vein thrombosis (PVT) and blood alpha-fetoprotein (AFP) levels. RESULTS: Using linear and logistic regression models, we found that C-reactive protein and PLR on single variables, were statistically significantly related to the tumour parameters. In a logistic regression final model, CRP was significantly related to MTD, AFP and PVT, and the Glasgow Index significantly related to MTD and AFP. Results of the area under the receiver operating characteristic curves (ROC), showed that the areas for PLR and CRP were statistically significant for high versus low MTD and for presence versus absence of PVT. CRP alone was significant for high versus low AFP. CONCLUSIONS: These analyses suggest that the prognostic usefulness of the inflammatory markers PLR and CRP (but not NLR) may be due to their reflection of parameter values for tumour growth and invasiveness.

C-Reactive Protein and Platelet-Lymphocyte Ratio as Potential Tumor Markers in Low-Alpha-Fetoprotein Hepatocellular Carcinoma.

The hepatocellular carcinoma (HCC) tumor marker alpha-fetoprotein (AFP) is only elevated in about half of the HCC patients, limiting its usefulness in following the effects of therapy or screening. New markers are needed. It has been previously noted that the inflammation markers C-reactive protein (CRP) and platelet-lymphocyte ratio (PLR) are prognostically important and may reflect HCC aggressiveness. We therefore examined these 2 markers in a low-AFP HCC cohort and found that for HCCs > 2 cm, both markers significantly rise with an increasing maximum tumor diameter (MTD). We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and Youden index value for each marker, and their area-under-the-curve values for each MTD group. Patients were dichotomized into 2 groups based on the CRP and PLR from the receiver-operating characteristic curve analysis. In the logistic regression models of the 4 different MTD patient groups, CRP and PLR levels were statistically significant to estimate MTD in univariate logistic regression models of MTD groups > 2 cm. CRP and PLR were then combined, and the combination was statistically significant to estimate MTD groups of 3-, 4-, and 5-cm cutoffs. CRP and PLR thus have potential as tumor markers for low-AFP HCC patients, and possibly for screening.

Macroscopic Portal Vein Thrombosis in HCC Patients.

Macroscopic portal vein invasion (PVT) by hepatocellular carcinoma (HCC) in the liver is one of the most important negative prognostic factors for HCC patients. The characteristics of a large cohort of such patients were examined. We found that the percent of patients with PVT significantly increased with increasing maximum tumor diameter (MTD), from 13.7% with tumors of MTD <5cm to 56.4% with tumors of MTD >10cm. There were similar numbers of HCC patients with very large tumors with and without PVT. Thus, MTD alone was insufficient to explain the presence of PVT, as were high AFP levels, since less than 50% of high AFP patients had PVT. However, the percent of patients with PVT was also found to significantly increase with increasing blood alpha-fetoprotein (AFP) levels and tumor multifocality. A logistic regression model that included these 3 factors together showed an odds ratio of 17.9 for the combination of MTD>5.0cm plus tumor multifocality plus elevated AFP, compared to low levels of these 3 parameters. The presence or absence of macroscopic PVT may therefore represent different HCC aggressiveness phenotypes, as judged by a significant increase in tumor multifocality and AFP levels in the PVT positive patients. Factors in addition to MTD and AFP must also contribute to PVT development.

C-reactive protein and hepatocellular carcinoma: analysis of its relationships to tumor factors.

C-reactive protein (CRP) is a blood marker for inflammation and is an independent prognostic factor for many human cancers. Combined with albumin levels, it forms the basis of the Glasgow Index for cancer prognosis. We reviewed the literature on CRP and HCC and also evaluated blood CRP levels and combination CRP plus albumin levels in a large HCC cohort. In order to understand the prognostic significance of CRP, we retrospectively examined a large HCC cohort and examined the relationship of CRP levels to tumor parameters. We report, that CRP alone and CRP plus albumin combined as well, significantly correlated with parameters of HCC aggressiveness, such as maximum tumor dimension (MTD), portal vein thrombosis (PVT) and blood alpha-fetoprotein (AFP) levels, both as individual parameters and all parameters together (Aggressiveness Index). This extends current thinking, to suggest a possible explanation for the usefulness of blood CRP levels in HCC prognostication.

HCC with low- and normal-serum alpha-fetoprotein levels.

A large database of 1773 HCC patients in Turkey was examined. 41.9% had alpha-fetoprotein (AFP) levels <20 IU/ml and an additional 16.123% had values between 20-100 IU/ml. This 58% of the cohort (<100 IU/ml AFP levels) was examined in detail. 66% of patients with small (<5 cm) HCCs had low AFP, compared to 49% of patients with larger (>5 cm) HCCs. The mean diameter (MTD) of larger MTD, low AFP tumors was 8.4cm. Therefore, factors other than AFP must contribute to HCC tumor growth. Larger tumors in low AFP patients had both higher platelet levels and increased PVT percent. Linear regression analysis for both MTD and multifocality showed that platelet numbers and presence of PVT were significant variables; whereas for PVT, significant variables were albumin, alkaline phosphatase and MTD. Comparisons between patients with AFP levels <20, 20-<100, 100-<1000 and >1000 IU/ml showed the most significant tumor finding was an increase in PVT percent between each group, and to a lesser extent, MTD. Thus, low- or normal-AFP HCCs constitute the majority of patients and have slightly lower MTD and much lower PVT percent than HCCs associated with elevated blood AFP levels. New, non-AFP markers are thus needed, especially for small HCCs.

Characteristics of Hepatocellular Carcinoma Aggressiveness Factors in Turkish Patients.

A large cohort of hepatocellular carcinoma (HCC) patients from several collaborating Turkish institutions were examined for the tumor parameters of maximum diameter (MTD), portal vein thrombosis (PVT), and α-fetoprotein (AFP) levels. A relationship was found between MTD and blood platelet levels. Patients with large ≥5 cm tumors who had normal platelet levels had significantly larger tumors, higher percent of PVT, and significantly lower blood total bilirubin and liver cirrhosis than similar ≥5 cm tumor patients having thrombocytopenia. A comparison of patients with and without PVT showed significantly larger tumors, greater multifocality, blood AFP, and C-reactive protein levels, and, interestingly, lower HDL levels in the patients with PVT. Fifty-eight percent of the total cohort had AFP levels ≤100 IU/mL (and 42.1% had values ≤20 IU/mL). These patients had significantly smaller tumors, less tumor multifocality and percent PVT, lower total bilirubin, and less cirrhosis. There was considerable geographic heterogeneity within Turkey in the patterns of HCC presentation, with areas of higher and lower hepatitis B virus, hepatitis D virus, cirrhosis, and tumor aggressiveness parameters. Turkish patients thus have distinct patterns of presentation, but the biological relationships between MTD and both platelets and bilirubin levels are similar to the relationships that have been reported in other ethnic patient groups.

Red blood cell distribution width as a non-invasive marker for the assessment of inflammation in non-alcoholic steatohepatitis.

BACKGROUND/AIMS: The aim of this study was to assess the association between red cell distribution width and inflammation in biopsy proven non-alcoholic steatohepatitis. METHODOLOGY: Fifty four subjects with non-alcoholic steatohepatitis and thirty nine controls were enrolled for the study. Liver biopsy specimens were scored by using non-alcoholic fatty liver disease activity score by a single experienced liver pathologist. RESULTS: Red cell distribution width was higher in the severe inflammation group in non-alcoholic steatohepatitis (p < 0.05). The areas under the receiver operating characteristic curves for the predictive performance of aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase and red cell distribution width in identifying inflammation in non-alcoholic steatohepatitis were 0.55 (0.41-0.68), 0.51 (0.37-0.64), 0.53 (0.39-0.67) and 0.73 (0.59-0.84) respectively and the differences of these values between red cell distribution width and other parameters were found to be statistically significant (p < 0.05). To determine the grading of inflammation, the specificity for using the red cell distribution width as an indicator in non-alcoholic steatohepatitis patients was calculated to be 73.3%, with 79.5% sen- sitivity. CONCLUSION: Red cell distribution width was a sensitive and specific method for the assessment of the inflammation in patients with non-alcoholic steatohepatitis.

Effects of ursodeoxycholic acid therapy on carotid intima media thickness, apolipoprotein A1, apolipoprotein B, and apolipoprotein B/A1 ratio in nonalcoholic steatohepatitis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a prevalent liver disease that is increasingly being associated with cardiovascular disease. Ursodeoxycholic acid (UDCA) may have antioxidant and anti-inflammatory activities, and may reduce liver injury in NASH. To date, no studies have assessed the efficacy of UDCA in carotid intima media thickness (CIMT), serum lipids, apolipoprotein A1 (apo A), apolipoprotein B (apo B), and apolipoprotein B/A1 (apo B/A1) ratios in patients with NASH. PATIENTS AND METHODS: In this prospective study, 30 patients with biopsy-proven NASH and 25 healthy adults as a control group were evaluated. None of the participants had diabetes, hypertension, or hyperlipidemia. Patients with NASH received UDCA 15 mg/kg/day for 6 months. BMI, waist circumference, homeostasis model assessment, lipids, apo A1, apo B, apo B/A1 ratios, and CIMT were analyzed before and after the treatment period. RESULTS: At the end of the study, there were no statistically significant changes in BMI or waist circumference. Liver enzymes decreased gradually. The homeostasis model assessment decreased from 3.4 ± 1.89 to 2.06 ± 1.68 (P < 0.001). No significant changes in the mean triglyceride, total cholesterol, low-density lipoprotein, or apo B levels were observed. The mean high-density lipoprotein (42.9 ± 7.1 vs. 45.5 ± 9.8; P = 0.037) and apo A1 (127.6 ± 17.7 vs. 135.9 ± 22.2; P = 0.02) increased significantly. Apo B/A1 ratios tended to decrease, but this decrease was not statistically significant. The mean CIMT decreased significantly (0.56 ± 0.15 vs. 0.47 ± 0.12; P = 0.001). CONCLUSION: UDCA treatment in NASH patients resulted in statistically significant reductions in the mean CIMT over a 6-month period. We believe that this benefit of UDCA may have resulted from decreased insulin resistance and increased serum high-density lipoprotein-apo A1 levels. However, larger, longer-term studies are needed to confirm this effect of UDCA in NASH.

Circulating microRNAs in patients with non-alcoholic fatty liver disease.

AIM: To identify novel non-invasive biomarkers for non-alcoholic fatty liver disease (NAFLD). METHODS: Twenty patients with histologically proven NAFLD and 20 controls were included. All NAFLD cases were scored using the NAFLD activity score. The relative expressions of miR-197, miR-146b, miR-10b, miR-181d, miR-34a, miR-122, miR-99a and miR-29a were analyzed using real-time polymerase chain reaction. RESULTS: Serum levels of miR-181d, miR-99a, miR-197 and miR-146b were significantly lower in biopsy-proven NAFLD patients than in the healthy controls. Serum levels of miR-197 and miR-10b were inversely correlated with degree of inflammation and miR-181d and miR-99a were inversely correlated with serum gamma glutamyl transferase levels in non-alcoholic steatohepatitis patients. CONCLUSION: NAFLD is associated with altered serum miRNA expression pattern. This study provides clues for defining the non-invasive diagnosis of NAFLD.

The Serum S100B Level as a Biomarker of Enteroglial Activation in Patients with Ulcerative Colitis.

Objective. Recent studies have demonstrated that enteric glial cells (EGC) participate in the homeostasis of the gastrointestinal tract. This study investigated whether enteroglial markers, including S100B protein and glial fibrillary acidic protein (GFAP), can serve as noninvasive indicators of EGC activation and disease activity in UC patients. Methods. This clinical prospective study included 35 patients with UC and 40 age- and sex-matched controls. The diagnosis of UC was based on standard clinical, radiological, endoscopic, and histological criteria. Clinical disease activity was evaluated using the Modified Truelove-Witts Severity Index. Serum samples were analyzed for human GFAP and S100B using commercial enzyme-linked immunosorbent assay kits. Results. GFAP was not detected in the serum of either UC patients or controls (P > 0.05). However, we found a significant (P < 0.001) decrease in the serum S100B levels in the UC patients. No correlation between the serum S100B level and the disease activity or duration was observed (P > 0.05). The serum S100B levels did not differ between UC patients with active disease (24 patients, 68.6%) or in remission (11 patients, 31.4%) (P > 0.05). Conclusions. Ulcerative colitis patients had significantly lower serum S100B levels, while GFAP was of no diagnostic value in UC patients.

Prolonged Cholestatic Jaundice Associated With Flurbiprofen.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely consumed drugs throughout the world for pain relief. Although the adverse effects of NSAIDs to the liver are well known, flurbiprofen-induced liver cholestasis is extremely rare. Herein, we present a patient with prolonged icterus that is associated with the use of flurbiprofen without causing ductopenia.

Noninvasive assessment of liver damage in chronic hepatitis B.

AIM: To evaluate the efficacy of the aspartate aminotransferase/platelet ratio index (APRI) and neutrophil-lymphocyte (N/L) ratio to predict liver damage in chronic hepatitis B (CHB). METHODS: We analyzed 89 patients diagnosed with CHB by percutaneous liver biopsy and 43 healthy subjects. Liver biopsy materials were stained with hematoxylin-eosin and Masson's trichrome. Patients' fibrosis scores and histological activity index (HAI) were calculated according to the Ishak scoring system. Fibrosis score was recognized as follows: F0-1 No /early-stage fibrosis, F2-6 significant fibrosis, F0-4 non-cirrhotic and F5-6 cirrhotic. Significant liver fibrosis was defined as an Ishak score of ≥ 2. APRI and N/L ratio calculation was made by blood test results. RESULTS: The hepatitis B and control group showed no difference in N/L ratios while there was a significant difference in terms of APRI scores (P < 0.001). Multiple logistic regression analysis revealed that the only independent predictive factor for liver fibrosis in CHB was platelet count. APRI score was significantly higher in cirrhotic patients than in non-cirrhotic patients. However, this significance was not confirmed by multiple logistic regression analysis. The optimum APRI score cut-off point to identify patients with cirrhosis was 1.01 with sensitivity, specificity, positive predictive value and negative predictive value of 62% (36%-86%), 74% (62%-83%), 29% (13%-49%) and 92% (82%-97%), respectively. In addition, correlation analyses revealed that N/L ratio has a negative and significant relationship with HAI (r = -0.218, P = 0.041). CONCLUSION: N/L ratio was negatively correlated with HAI. APRI score may be useful to exclude cirrhosis in CHB patients.

Neutrophil-lymphocyte ratio as a predictor of disease severity in ulcerative colitis.

BACKGROUND: Blood neutrophil-to-lymphocyte (N/L) ratio is an indicator of the overall inflammatory status of the body, and an alteration in N/L ratio may be found in ulcerative colitis (UC) patients. The aims of this study were to investigate the utility of N/L ratio as a simple and readily available predictor for clinical disease activity in UC. METHODS: Twenty-six patients and 28 healthy controls were enrolled in the study. The neutrophil and lymphocyte counts were recorded, and the N/L ratio was calculated from these parameters. The extent of disease classified according to the Montreal classification, clinical disease activity was evaluated using a modified Truelove-Witts severity index, and endoscopic disease activities were classified according to Schroder et al. RESULTS: The serum N/L ratios of active patients were significantly higher than those of inactive UC and controls (P < 0.001). The optimum N/L ratio cut-off point for active UC was 2.47. There was no significant difference between inflammation parameters, disease extension, and disease activity. CONCLUSION: Our results demonstrate that N/L ratio is higher in patients with active UC compared with controls and UC patients in remission and a cut-off value of 2.47 can be used to identify patients with active ulcerative colitis.

Investigation of genome instability in exfoliated colonic epithelial cells and in mitogen-stimulated lymphocytes of patients with ulcerative colitis.

OBJECTIVE: The present study aimed to evaluate the micronucleus (MN), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) in the mitogen-stimulated lymphocytes of patients with ulcerative colitis (UC). In addition, we assessed MN frequency in exfoliated colonic epithelial cells obtained from both the diseased and healthy colonic mucosa of patients. DESIGN: The study was conducted in 22 newly diagnosed patients with UC and in 22 healthy controls. MN, NPB and NBUD values scored in binucleated (BN) cells were obtained from the mitogen-stimulated lymphocytes of patients and control subjects. In addition, the MN values in exfoliated epithelial cells obtained from the diseased and healthy colonic mucosa of patients were evaluated. RESULTS: We found significantly higher MN, NPB and NBUD frequencies in the BN cells of patients with UC than in those of the control subjects (1.61 ± 0.75 vs. 0.89 ± 0.29, 3.93 ± 1.91 vs. 1.39 ± 1.10, and 1.55 ± 0.89 vs. 0.64 ± 0.48, p = 0.001). Also, a statistically significant difference was found between MN frequencies obtained from the diseased and healthy colonic mucosa of patients (1.07 ± 0.46 vs. 0.59 ± 0.21, p = 0.001). No significant relationship was found between age and MN frequency in patients with UC (r = 0.076, p = 0.735). CONCLUSION: Increased MN, NPB and NBUD frequencies observed in both the lymphocytes and exfoliated colonic epithelial cells obtained from patients with UC may reflect genomic instability.

Endoscopic topical application of Ankaferd Blood Stopper® in gastrointestinal bleeding.

AIM: This was a prospective study investigating the efficacy of Ankaferd Blood Stopper(®) (ABS), an herbal preparation, in patients with upper gastrointestinal (UGI) bleeding. MATERIALS AND METHODS: A total of 30 patients (22 male, 8 female) who had UGI bleeding (with differing causes) were included in the study. ABS was used to stop the bleeding. RESULTS: Primary hemostasis was achieved in 26 of the 30 cases. CONCLUSIONS: ABS is an effective and safe agent to use in patients with UGI bleeding.