Murat Akyildiz

Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease.

Aim To investigate the efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease (NAFLD) patients. Methods This is an open-label, randomized, a single-center study. Sixty-four patients, with impaired glucose metabolism and elevated alanine aminotransferase for at least 6 months before enrollment and NAFLD activity score at least 5 in liver biopsy, were randomized as group 1 and received metformin 1700 mg/day, group 2 received rosiglitazone 4 mg/day, and group 3 received a combination of metformin 1700 mg/day and rosiglitazone 4 mg/day for 12 months. Results Baseline demographic and laboratory findings were similar in all the three groups, except baseline insulin level that was significantly higher in group 1 and group 3 versus group 2 (P<0.05). Serum transaminase levels showed a significant decrease after treatment in both group 2 and group 3. Serum &ggr;-glutamyl transpeptidase levels decreased significantly only in the group 3. However, there was no significant change in liver tests of group 1. Postprandial glucose levels showed significant decrease in all of the three groups. Homeostasis model assessment-insulin resistance was reduced significantly in only group 2. NAFLD score was significantly decreased on follow-up biopsy of the patients in group 2 and group 3. Fibrosis did not change significantly after the treatment. Conclusion Rosiglitazone therapy seems to be more effective in metabolic control and histological improvement in NAFLD patients with impaired glucose metabolism.

Adefovir dipivoxil therapy in liver transplant recipients for recurrence of hepatitis B virus infection despite lamivudine plus hepatitis B immunoglobulin prophylaxis

Background:  Treatment of post‐transplantation recurrence of hepatitis B virus (HBV) infection despite prophylaxis with hepatitis B immunoglobulin (HBIG) and lamivudine combination therapy is not easy. Because HBV reinfection has a severe course and could result in graft failure in liver transplant recipients, prompt medication is essential. Herein is reported the authors’ experience with adefovir dipivoxil (AD) therapy in 11 liver transplant recipients who had HBV reinfection despite the administration of lamivudine and HBIG.

Live donor liver transplantation for acute liver failure.

Background. Acute liver failure (ALF) carries a high mortality unless urgent orthotopic liver transplantation (OLT) is performed on time. Live donors are utilized to treat this irreversible condition first in pediatric cases and then in adults. Herein, we aimed to report our experience with live donors for ALF in a country of a deceased donor organ donation rate is only 1.5 per million people. Methods. Among the 245 live donor liver transplantations (LDLT) performed from June 1999 to December 2005, 14 of them (6%) were performed for ALF in 8 pediatric and 6 adult cases. Right lobes were harvested for the adult cases whereas left lateral segments were harvested for pediatric cases, except one child transplanted with a right lobe graft. The etiology of the disease was; acute hepatitis B in four cases, hepatitis A in three cases, Wilson disease two cases, autoimmune hepatitis in two cases, and was unknown in three cases. Results. Three-year graft and patient survival is 79% for these series. Five of the six adult patients and six of the eight pediatric cases survived after transplantation. There was not any donor mortality or major morbidity. Conclusions. LDLT offers a safe and effective modality of treatment for ALF for both pediatric and adult patients to overcome the problem of organ shortage especially in countries where the chance of receiving an organ from a deceased donor is low.

AFP level and histologic differentiation predict the survival of patients with liver transplantation for hepatocellular carcinoma.

BACKGROUND In liver transplantation or resection for hepatocellular carcinoma (HCC), patient selection depends on morphological features. In patients with HCC, we performed a clinicopathological analysis of risk factors that affected survival after liver transplantation. METHODS In 389 liver transplantations performed from 2004 to 2010, 102 were for HCC patients. Data were collected retrospectively from the Organ Transplantation Center Database. Variables were as follows: age, gender, preoperative alpha-fetoprotein (AFP) levels, Child-Pugh and MELD scores, prognostic staging criteria (Milan and UCSF), etiology, number of tumors, the largest tumor size, total tumor size, multifocality, intrahepatic portal vein tumor thrombosis, bilobarity, and histological differentiation. RESULTS One hundred and two patients were evaluated. The 5-year overall survival rate was 56.5%. According to the UCSF criteria, 63% of the patients were within and 37% were beyond UCSF (P=0.03). Ten patients were excluded (one with fibrolamellary HCC and 9 because of early postoperative death without HCC recurrence), and 92 patients were assessed. The mean age of the patients was 56.5+/-6.9 years. Sixty-two patients underwent living donor liver transplantations. The mean follow-up time was 29.4+/-22.6 months. Fifteen patients (16.3%) died in the follow-up period due to HCC recurrence. Univariate analysis showed that AFP level, intrahepatic portal vein tumor thrombosis, histologic differentiation and UCSF criteria were significant factors related to survival and tumor recurrence.The 5-year estimated overall survival rate was 62.2% in all patients. According to the UCSF criteria, and the 5-year overall survival rate was 66.7% within and 52.7% beyond the criteria (P=0.04). Multivariate analysis showed that AFP level and poor differentiation were independent factors. CONCLUSIONS For proper patient selection in liver transplantation for HCC, prognostic criteria related to tumor biology (especially AFP level and histological differentiation) should be considered. Poor differentiation and higher AFP levels are indicators of poor prognosis after liver transplantation.

Association between hepatitis B and hepatocellular carcinoma recurrence in patients undergoing liver transplantation.

BACKGROUND/AIMS Hepatitis B virus (HBV) and hepatocellular carcinoma (HCC) recurrences affect both patient and graft survivals post-orthotopic liver transplantation (OLT) in HBV patients with HCC. We analyzed the relationship between HBV and HCC recurrence in a large cohort of HBV-OLT patients with versus without HCC. METHODS Two hundred eighty-seven HBV patients with OLT (72 also with HCC) were included in the study. Mean follow-up in the post-OLT period was 31.7 +/- 24.7 (range, 3-119) months. RESULTS Post-OLT HBV recurrence observed in 10.1% of patients was more prevalent among the HCC group; 23.6% versus 5.5% in patients with and without HCC, respectively. The mean interval for the development of HBV recurrence was 39.5 +/- 28.5 (range, 2-99) months. Among 72 HCC patients, 8 patients (11.1%) had recurrent HCC, and 7 of them also had HBV recurrence. The mean interval for the development of HCC recurrence was 11.2 +/- 7.85 (range, 2-23) months after OLT. OLT patients with HCC with tumors exceeding the Milan criteria had worse 1-, 3-, and 5-year survival rates than patients with HCC meeting the Milan criteria. HBV and HCC recurrence-free survivals were significantly lower in patients with HCC and HBV recurrence, respectively. In the 7 patients with both HCC and HBV recurrence, mean HBV recurrence time was 9.42 +/- 6.75 months and mean HCC recurrence time was 9.57 +/- 6.75 months. There was a strong correlation between HBV and HCC recurrence times. Cox proportional hazards regression analysis showed that only HCC recurrence was a significant independent predictor of HBV recurrence (P < .001; hazard ratio [HR] = 26.94; 95% confidence interval [CI] = 10.81-67.11). On the other hand, HBV recurrence (P = .013; HR = 5.80; 95% CI = 1.45-23.17) and nodule count (P = .014; HR = 13.08; 95% CI = 1.70-100.83) were significant predictors of HCC recurrence. CONCLUSIONS HBV and HCC recurrences demonstrate a close relationship in patients with OLT.

The Predictive and Prognostic Significance of c-erb-B2, EGFR, PTEN, mTOR, PI3K, p27, and ERCC1 Expression in Hepatocellular Carcinoma

Background Hepatocellular carcinoma (HCC) is the fifth most common fatal cancer and an important healthcare problem worldwide. There are many studies describing the prognostic and predictive effects of epidermal growth factor receptor 2 (c-erb-B2) and epidermal growth factor receptor 1 (EGFR), transmembrane tyrosine kinases that influence cell growth and proliferation in many tumors. Objectives The current study aimed to investigate the expression levels of c-erb-B2, EGFR, PTEN, mTOR, PI3K, p27, and ERCC1 in hepatocellular carcinoma (HCC) and their correlation with other clinicopathologic features. Patients and Methods Fifty HCC cases were stained immunohistochemically with these markers. Correlations between the markers and clinicopathologic characteristics and survival rates were analyzed. Results No membranous c-erb-B2 staining was seen, whereas cytoplasmic positivity was present in 92% of HCC samples, membranous EGFR was observed in 40%, PI3K was found in all samples, and mTOR was seen in 30%, whereas reduced or absent PTEN expression was observed in 56% of samples and loss of p27 was seen in 92% of the cases. c-erb-B2 and mTOR overexpression, as well as reduced expression of p27, all correlated with multiple tumors (P = 0.041, P < 0.001, and P < 0.001, respectively). P27 loss, and mTOR and EGFR positivity were significantly correlated with AFP (P = 0.047, P = 0.004, and P = 0.008, respectively). Angiolymphatic invasion was more commonly seen in EGFR- and ERCC1-positive cases (P = 0.003 and P = 0.005). EGFR was also correlated with histological grade (P = 0.039). No significant correlations were found among PTEN , PI3K, and the clinicopathological parameters. Disease-free or overall survival rates showed significant differences among therapy modalities, AFP levels, angiolymphatic or lymph node invasions, and ERCC1 and p27 expression levels (P < 0.05). Conclusions c-erb-B2, EGFR, mTOR, ERCC1 overexpression levels, and loss of p27 may play roles in hepatocarcinogenesis and may be significant predictors of aggressive tumor behavior. These markers were found to be correlated with certain clinicopathologic features, therapy modalities, and survival rates in the current study. These findings may help in planning new, targeted treatment strategies .

Living donor liver transplantation for obese patients: Challenges and outcomes

Living donor liver transplantation (LDLT) is an accepted option for end‐stage liver disease, particularly in countries in which there are organ shortages. However, little is known about LDLT for obese patients. We sought to determine the effects of obesity on pretransplant living donor selection for obese recipients and their outcomes. On the basis of body mass index (BMI) values, 148 patients were classified as normal weight (N), 148 were classified as overweight (OW), and 74 were classified as obese (O). O recipients had significantly greater BMI values (32.1 ± 1.6 versus 23.2 ± 1.9 kg/m2, P < 0.001) and received larger actual grafts (918.9 ± 173 versus 839.4 ± 162 g, P = 0.002) than recipients with normal BMI values. Donors who donated to O recipients had a greater mean BMI (26.3 ± 3.8 kg/m2) than those who donated to N recipients (24.4 ± 3.2 kg/m2, P = 0.001). Although O recipients were more likely to face some challenges in finding a suitable living donor, there were no differences in graft survival [hazard ratio (HR) = 0.955, 95% confidence interval (CI) = 0.474‐1.924, P = 0.90] or recipient survival (HR = 0.90, 95% CI = 0.56‐1.5, P = 0.67) between the 3 groups according to an adjusted Cox proportional hazards model. There were no significant differences in posttransplant complication rates between the 3 recipient groups or in the morbidity rates for the donors who donated to O recipients versus the donors who donated to OW and N recipients (P = 0.26). Therefore, we recommend that obese patients undergo pretransplant evaluations. If they are adequately evaluated and selected, they should be considered for LDLT. Liver Transpl 20:311‐322, 2014.

Living donor liver hilar variations: surgical approaches and implications

BACKGROUND Varied vascular and biliary anatomies are common in the liver. Living donor hepatectomy requires precise recognition of the hilar anatomy. This study was undertaken to study donor vascular and biliary tract variations, surgical approaches and implications in living liver transplant patients. METHODS Two hundred living donor liver transplantations were performed at our institution between 2004 and 2009. All donors were evaluated by volumetric computerized tomography (CT), CT angiography and magnetic resonance cholangiography in the preoperative period. Intraoperative ultrasonography and cholangiography were carried out. Arterial, portal and biliary anatomies were classified according to the Michels, Cheng and Huang criteria. RESULTS Classical hepatic arterial anatomy was observed in 129 (64.5%) of the 200 donors. Fifteen percent of the donors had variation in the portal vein. Normal biliary anatomy was found in 126 (63%) donors, and biliary tract variation in 70% of donors with portal vein variations. In recipients with single duct biliary anastomosis, 16 (14.4%) developed biliary leak, and 9 (8.1%) developed biliary stricture; however more than one biliary anastomosis increased recipient biliary complications. Donor vascular variations did not increase recipient vascular complications. Variant anatomy was not associated with an increase in donor morbidity. CONCLUSIONS Living donor liver transplantation provides information about variant hilar anatomy. The success of the procedure depends on a careful approach to anatomical variations. When the deceased donor supply is inadequate, living donor transplantation is a life-saving alternative and is safe for the donor and recipient, even if the donor has variant hilar anatomy.

Macrophage migration inhibitory factor expression and MIF gene -173 G/C polymorphism in nonalcoholic fatty liver disease.

Aim To investigate the macrophage migration inhibitory factor (MIF) expression and −173 G/C polymorphism of the MIF gene in nonalcoholic fatty liver disease (NAFLD). Method Ninety-one patients with diagnosis of NAFLD and 104 healthy controls were included in the study. MIF −173 G/C polymorphism was detected using the PCR–restriction fragment length polymorphism based method. NAFLD was stratified as nonalcoholic steatohepatitis (NASH), probable NASH and steatosis, respectively in groups 1, 2 and 3, according to NAFLD Activity Score. MIF expression was detected by immunohistochemistry staining. Results Mean age of the patients was 50.1±9.6 years, and 54 of them were male. Serum alanine aminotransferase and aspartate aminotransferase were 50/83, 42/63 and 31/32, respectively in groups 1, 2 and 3, (P<0.05). Both the MIF expression of hepatocytes and mononuclear cells were more prominent in groups 1 and 2 than group 3. There was no correlation between MIF expression of hepatocytes and fibrosis stage. However, MIF expression of mononuclear cells significantly increased according to fibrosis stage (P<0.05, R : 0.2). There was no significant correlation between MIF genotype and MIF expression in the liver. Conclusion MIF expression is significantly increased especially by mononuclear cells in liver tissue of patients with NASH secondary to inflammation. Thus, it should be considered as a consequence not a causal factor.

The efficacy of ranitidine bismuth citrate, amoxicillin and doxycycline or tetracycline regimens as a first line treatment for Helicobacter pylori eradication.

BACKGROUND The eradication rates of Helicobacter pylori (H. pylori) clearly decreased with standard PPI-based triple therapies. AIM To assess the efficacy of two different triple therapies consisting of ranitidine bismuth citrate-amoxicillin-doxycycline and ranitidine bismuth citrate-amoxicillin-tetracycline combinations as a first line treatment option. METHODS One hundred and fifteen consecutive dyspeptic patients in whom H. pylori infection was diagnosed for the first time were enrolled in this study. The patients were randomized into two groups. Group 1 (n=57) was assigned to receive a 14-day triple therapy consisting of ranitidine bismuth citrate 400 mg (b.i.d.), amoxicillin 1 g (b.i.d) and doxycycline 100 mg (b.i.d.). Group 2 (n=58) was assigned to receive a 14-day triple therapy consisting of ranitidine bismuth citrate 400 mg (b.i.d.), amoxicillin 1 g (b.i.d.) and tetracycline 500 mg (q.i.d.). RESULTS The eradication was achieved in 45.7% (21/46) and 40.8% (20/49) of the patients in group 1 and group 2, according to per protocol analysis. The intention-to-treat eradication rates were 36.8% (21/57) and 34.5% (20/58) in group 1 and group 2, respectively. CONCLUSIONS Two-week therapy with neither ranitidine bismuth citrate-amoxicillin-doxycycline nor ranitidine bismuth citrate-amoxicillin-tetracycline is adequately effective for H. pylori eradication as a first line therapy.