International Journal of Hepatology The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. The Value of Serum Midkine Level in Diagnosis of Hepatocellular Carcinoma Sun, 08 Feb 2015 06:30:23 +0000 Background and Aim. Identification of sensitive biomarkers to improve early diagnosis of HCC is needed. We aimed to evaluate serum midkine (MDK) as a biomarker for HCC diagnosis. Patients and Methods. 40 HCCs, 30 liver cirrhosis patients, and 30 healthy subjects were enrolled. Serum MDK using ELISA was measured in all included subjects. Results. Serum MDK was significantly elevated in HCC group compared to cirrhotic and healthy control groups (0.625 versus 0.15 and 0.125 ng/mL), respectively. No significant association was found between MDK and either BCLC stage, tumor diameter, tumor number, or AFP level. Receiver operating characteristic curve showed that best cutoff for MDK and AFP was 0.387 and 88.5 ng/mL, respectively. Area under the curve of MDK was significantly larger than that of AFP (0.941 versus 0.671). The sensitivity of MDK at 0.387 ng/mL for HCC diagnosis was significantly higher than that of AFP at cutoffs 20, 88.5, and 200 ng/mL (92.5 versus 62.5, 40, and 25%), respectively. Sensitivity of MDK reached 93.3% in patients with AFP <20 ng/mL. Moreover, MDK at 0.387 ng/mL had significant better sensitivity than AFP at 20 ng/mL in distinguishing HCC from BCLC 0/A (90 versus 40%). Conclusion. Serum MDK might be a potential diagnostic marker for HCC particularity in its early stages. Karim Y. A. Shaheen, Abeer I. Abdel-Mageed, Eslam Safwat, and Ashraf M. AlBreedy Copyright © 2015 Karim Y. A. Shaheen et al. All rights reserved. Mystery of Hepatitis E Virus: Recent Advances in Its Diagnosis and Management Mon, 19 Jan 2015 12:30:19 +0000 Mysterious aspects of the long presumed to be well-known hepatitis E virus (HEV) have recently surfaced that distinguish it from other hepatotropic viruses. It is a cause of chronic hepatitis in immunosuppressed patients. It has human to human transmission through blood and mantains high seroprevalence in blood donors. HEV has also been found to occur more frequently in the West in those without a history of travel to endemic countries. It has varied extrahepatic manifestations and has multiple non-human reservoirs including pigs and rats. Considering these recent discoveries, it appears odd that HEV is not sought more frequently when working up acute and chronic hepatitis patients. The disease is particularly severe among pregnant women and has a high attack rate in young adults. What adds to its ambiguity is the absence of a well-established diagnostic criteria for its detection and that there is no specific antiviral drug for hepatitis E, except for isolated cases where ribavirin or pegylated interferon alpha has been used with occasional success. This review paper discusses the recent advances in the knowledge of the virus itself, its epidemiology, diagnostic approach and prevention, and the treatment options available. Aftab Ahmed, Ijlal Akbar Ali, Hira Ghazal, Javid Fazili, and Salman Nusrat Copyright © 2015 Aftab Ahmed et al. All rights reserved. Circulating MicroRNAs in Plasma of Hepatitis B e Antigen Positive Children Reveal Liver-Specific Target Genes Wed, 17 Dec 2014 07:45:33 +0000 Background and Aim. Hepatitis B e antigen positive (HBeAg-positive) children are at high risk of severe complications such as hepatocellular carcinoma and cirrhosis. Liver damage is caused by the host immune response to infected hepatocytes, and we hypothesise that specific microRNAs play a role in this complex interaction between virus and host. The study aimed to identify microRNAs with aberrant plasma expressions in HBeAg-positive children and with liver-specific target genes. Methods. By revisiting our previous screen of microRNA plasma levels in HBeAg-positive and HBeAg-negative children with chronic hepatitis B (CHB) and in healthy controls, candidate microRNAs with aberrant plasma expressions in HBeAg-positive children were identified. MicroRNAs targeting liver-specific genes were selected based on bioinformatics analysis and validated by qRT-PCR using plasma samples from 34 HBeAg-positive, 26 HBeAg-negative, and 60 healthy control children. Results. Thirteen microRNAs showed aberrant plasma expressions in HBeAg-positive children and targeted liver-specific genes. In particular, three microRNAs were upregulated and one was downregulated in HBeAg-positive children compared to HBeAg-negative and healthy control children, which showed equal levels. Conclusion. The identified microRNAs might impact the progression of CHB in children. Functional studies are warranted, however, to elucidate the microRNAs’ role in the immunopathogenesis of childhood CHB. Thilde Nordmann Winther, Kari Stougaard Jacobsen, Aashiq Hussain Mirza, Ida Louise Heiberg, Claus Heiner Bang-Berthelsen, Flemming Pociot, and Birthe Hogh Copyright © 2014 Thilde Nordmann Winther et al. All rights reserved. E. coli Induced Experimental Model of Primary Biliary Cirrhosis: At Last Tue, 16 Dec 2014 11:28:17 +0000 Recurrent urinary tract infections (UTI) have been considered potential triggers of primary biliary cirrhosis (PBC), an autoimmune cholestatic liver disease characterised by progressive destruction of intrahepatic bile ducts. Additional support for the link made between PBC and UTI was based on early observations of recurrent episodes of bacteriuria in female patients with PBC. A series of large epidemiological studies demonstrated a strong correlation between recurrent UTI and PBC, initiating a series of studies investigating the role of Escherichia coli (E. coli, the most prevalent organism isolated in women with UTI) as a trigger of PBC. Immunological evidence of B- and T-cell cross-reactive responses implicating PBC-specific autoantigens and E. coli mimics have been clearly demonstrated, adding support to the notion that E. coli is a potential infectious inducer of PBC in susceptible individuals. One of the major limitations in proving the E. coli/PBC association was the lack of reliable E. coli-infected animal models of PBC. This review provides an overview of the evidence linking this infectious agent with PBC and discusses the pros and cons of a recently developed E. coli-infected animal model of PBC. Andreas L. Koutsoumpas, Daniel S. Smyk, and Dimitrios P. Bogdanos Copyright © 2014 Andreas L. Koutsoumpas et al. All rights reserved. The Mind and Liver Test: A New Approach to the Diagnosis of Minimal Hepatic Encephalopathy in Resource-Poor Settings Mon, 08 Dec 2014 12:52:14 +0000 Background and Aims. Minimal hepatic encephalopathy (MHE) is diagnosed using neuropsychometric tests or neurophysiological tests that are either inapplicable to illiterate patient population in resource-poor settings or require sophisticated and expensive equipment. The available tests assess discrete domains of mental impairment. Our aim was (a) to design a neuropsychometric test that measures all domains of mental impairment in MHE using one metric; (b) to evaluate its sensitivity, specificity, and reproducibility. Methods. The mind and liver test (MALT), a psychometric test assessing cognition, memory, and psychometric impairment, each on a scale of 20, was designed keeping in mind the requirements of a universal test. 40 cirrhotics and 36 controls were subjected to critical flicker frequency (CFF) and MALT in same sitting. ROC curve was plotted for MALT using CFF as gold standard. Bland-Altman plot was used to find test-retest agreement. Results. CFF values and MALT scores varied significantly between the cases and the controls . MALT was 94% sensitive and 83% specific. Using ROC with CFF as gold standard, the AUC for diagnosis of MHE using MALT score was 0.89. Test-retest agreement was high (ICC = 0.89). Conclusion. In this pilot study, MALT proved to be highly sensitive, specific, inexpensive, and reproducible. Saurav Das, Sajjadh M. J. Ali, James Seward, and Jayanthi Venkataraman Copyright © 2014 Saurav Das et al. All rights reserved. IFNL4 ss469415590 Variant Is Associated with Treatment Response in Japanese HCV Genotype 1 Infected Individuals Treated with IFN-Including Regimens Mon, 08 Dec 2014 12:36:41 +0000 Aim. Eradication of hepatitis C virus (HCV) is still challenging even if interferon- (IFN-) free regimens with direct-acting antiviral agents (DAAs) for HCV-infected individuals are available in clinical practice. IFNL4 is a newly described protein, associated with human antiviral defenses. We investigated whether IFNL4 ss469415590 variant has an effect on the prediction of treatment response in HCV-infected patients treated with IFN-including regimens. Patients and Methods. In all, 185 patients infected with HCV genotype 1 treated with peg-IFN plus ribavirin, with or without telaprevir, were genotyped for IFNL4 ss469415590. We retrospectively investigated whether the role of IFNL4 ss469415590 variant and other factors could predict sustained virological response (SVR) in Japanese patients infected with HCV genotype 1. Results. There were 65.7%, 31.5%, and 2.8% patients in the IFNL4 ss469415590 TT/TT, TT/-G, and -G/-G groups, respectively. SVR rates were 82.1% or 49.3% in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively. IFNL4 ss469415590 variant and HCV viral loads or IFNL4 ss469415590 variant and early virological response were better predictors of SVR in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively. Conclusion. In the era of DAAs, measurement of IFNL4 ss469415590 variant could help the prediction of SVR in Japanese HCV genotype 1 infected individuals treated with IFN-including regimens. Tatsuo Miyamura, Tatsuo Kanda, Shingo Nakamoto, Makoto Arai, Masato Nakamura, Shuang Wu, Xia Jiang, Reina Sasaki, Yuki Haga, Shin Yasui, Yoshihiko Ooka, Tetsuhiro Chiba, Fumio Imazeki, Shigeru Mikami, and Osamu Yokosuka Copyright © 2014 Tatsuo Miyamura et al. All rights reserved. Central Portalization Correlates with Fibrosis but Not with Risk Factors for Nonalcoholic Steatohepatitis in Steatotic Chronic Hepatitis C Sun, 30 Nov 2014 00:10:09 +0000 Concomitant steatosis in chronic hepatitis C is associated with fibrosis and unfavorable treatment outcome. Central zone injury in nonalcoholic steatohepatitis (NASH) manifests as central portalization, with centrizonal microvessels and ductular reaction. We investigated whether central portalization in steatotic HCV biopsies would identify patients with metabolic risk factors for NASH. Liver biopsies with chronic hepatitis C and >10% steatosis were evaluated for the degree of steatosis, zonation of steatosis, fibrosis, and nonalcoholic fatty liver disease (NAFLD) activity score. The presence of centrizonal microvessels, sinusoidal capillarization, ductular reaction, and CK7 positive intermediate-phenotype hepatocytes were evaluated by CD34 and CK7 immunostain. The degree of steatosis and fibrosis showed a positive correlation. Additional positive correlations were noted between centrizonal angiogenesis and NAFLD activity score and central portalization and fibrosis. However, neither central portalization nor zonation of steatosis identified patients with metabolic risk factors for NASH. Therefore, central portalization cannot be used as a surrogate marker to identify patients with metabolic risk factors for NASH in steatotic HCV biopsies. The mechanism of centrizonal injury in steatotic HCV hepatitis is not solely attributable to the metabolic risk factors for NASH. Hwajeong Lee, Sanaz Ainechi, Karen Dresser, and Elizabeth M. Kurian Copyright © 2014 Hwajeong Lee et al. All rights reserved. Clinical Features of Adult Patients with Acute Hepatitis B Virus Infection Progressing to Chronic Infection Thu, 02 Oct 2014 12:49:09 +0000 Background. Information regarding the progression of acute hepatitis B virus (HBV) infection to chronic infection in adults is scarce. Methods. Twenty-five adult patients with acute HBV infection (14 men and 11 women, 18–84 years old), whose clinical features progressed to those of chronic infection (group A) or did not (group B), were studied retrospectively. Results. There were 3 and 22 patients in groups A and B, respectively. Two of the 3 patients of group A lacked the typical symptoms of acute hepatitis. No differences were found between groups with respect to age, sex, or HBV genotypes. However, total bilirubin and alanine aminotransaminase levels were significantly lower in group A. Conclusions. Three of the 25 adult patients with acute HBV infection progressed to chronic infection. Hepatitis was mild in these patients. Patients with mild acute hepatitis B or unapparent HBV infection may have a higher risk of progressing to chronic infection. Kojiro Michitaka, Atsushi Hiraoka, Yoshio Tokumoto, Keiko Ninomiya, Tomoyuki Ninomiya, Norio Horiike, Masanori Abe, and Yoichi Hiasa Copyright © 2014 Kojiro Michitaka et al. All rights reserved. Fructose Induced Endotoxemia in Pediatric Nonalcoholic Fatty Liver Disease Sun, 28 Sep 2014 10:23:02 +0000 In preclinical studies of fructose-induced NAFLD, endotoxin appears to play an important role. We retrospectively examined samples from three pediatric cohorts (1) to investigate whether endotoxemia is associated with the presence of hepatic steatosis; (2) to evaluate postprandial endotoxin levels in response to fructose beverage in an acute 24-hour feeding challenge, and (3) to determine the change of fasting endotoxin amounts in a 4-week randomized controlled trial comparing fructose to glucose beverages in NAFLD. We found that adolescents with hepatic steatosis had elevated endotoxin levels compared to obese controls and that the endotoxin level correlated with insulin resistance and several inflammatory cytokines. In a 24-hour feeding study, endotoxin levels in NAFLD adolescents increased after fructose beverages (consumed with meals) as compared to healthy children. Similarly, endotoxin was significantly increased after adolescents consumed fructose beverages for 2 weeks and remained high although not significantly at 4 weeks. In conclusion, these data provide support for the concept of low level endotoxemia contributing to pediatric NAFLD and the possible role of fructose in this process. Further studies are needed to determine if manipulation of the microbiome or other methods of endotoxin reduction would be useful as a therapy for pediatric NAFLD. Ran Jin, Andrew Willment, Shivani S. Patel, Xiaoyan Sun, Ming Song, Yanci O. Mannery, Astrid Kosters, Craig J. McClain, and Miriam B. Vos Copyright © 2014 Ran Jin et al. All rights reserved. Diagnosis of Spontaneous Bacterial Peritonitis and an In Situ Hybridization Approach to Detect an “Unidentified” Pathogen Tue, 15 Jul 2014 00:00:00 +0000 Spontaneous bacterial peritonitis (SBP) is a frequent and severe complication in cirrhotic patients with ascites. Although identifying the pathogen(s) plays a major role in the management of infectious diseases, ascitic fluid cultures often show negative results in patients with clinical signs and symptoms of SBP, and ascitic fluid cell analyses are the gold standard method for diagnosing SBP. SBP is generally diagnosed based on an increased number of polymorphonuclear neutrophils in the ascitic fluid (250/mm3), and the identification of the causal pathogen may not be given consideration. We newly developed an in situ hybridization (ISH) method to provide early and direct evidence of bacterial infection in ascites in patients with SBP. This paper will review the diagnosis of SBP, including our novel approach with ISH method to detect bacterial DNA in SBP ascitic fluid. Hirayuki Enomoto, Shin-ichi Inoue, Akio Matsuhisa, and Shuhei Nishiguchi Copyright © 2014 Hirayuki Enomoto et al. All rights reserved. Cholangiocarcinoma with respect to IgG4 Reaction Tue, 15 Jul 2014 00:00:00 +0000 IgG4 reactions marked by infiltration of IgG4-positive plasma cells in affected organs occur in cancer patients and in patients with IgG4-related diseases. Extrahepatic cholangiocarcinomas including gall bladder cancer are often accompanied by significant IgG4 reactions; these reactions show a negative correlation with CD8-positive cytotoxic T cells, suggesting that the evasion of immune surveillance is associated with cytotoxic T cells. The regulatory cytokine IL-10 may induce IgG4-positive plasma cell differentiation or promote B cell switching to IgG4 in the presence of IL-4. Cholangiocarcinoma cells may function as nonprofessional antigen presenting cells that indirectly induce IgG4 reactions via the IL-10-producing cells and/or these may act as Foxp3-positive and IL-10-producing cells that directly induce IgG4 reactions. Moreover, IgG4-related disease is a high-risk factor for cancer development; IgG4-related sclerosing cholangitis (IgG4-SC) cases associated with cholangiocarcinoma or its precursor lesion biliary intraepithelial neoplasia (BilIN) have been reported. IgG4-positive cell infiltration is an important finding of IgG4-SC but is not a histological hallmark of IgG4-SC. For the diagnosis of IgG4-SC, its differentiation from cholangiocarcinoma remains important. Kenichi Harada and Yasuni Nakanuma Copyright © 2014 Kenichi Harada and Yasuni Nakanuma. All rights reserved. Genetic Diseases That Predispose to Early Liver Cirrhosis Mon, 14 Jul 2014 11:08:54 +0000 Inherited liver diseases are a group of metabolic and genetic defects that typically cause early chronic liver involvement. Most are due to a defect of an enzyme/transport protein that alters a metabolic pathway and exerts a pathogenic role mainly in the liver. The prevalence is variable, but most are rare pathologies. We review the pathophysiology of such diseases and the diagnostic contribution of laboratory tests, focusing on the role of molecular genetics. In fact, thanks to recent advances in genetics, molecular analysis permits early and specific diagnosis for most disorders and helps to reduce the invasive approach of liver biopsy. Manuela Scorza, Ausilia Elce, Federica Zarrilli, Renato Liguori, Felice Amato, and Giuseppe Castaldo Copyright © 2014 Manuela Scorza et al. All rights reserved. Intraductal Papillary Neoplasms of the Bile Duct Sun, 18 May 2014 14:01:15 +0000 Intraductal papillary neoplasm of the bile duct (IPNB) is a rare variant of bile duct tumors characterized by papillary growth within the bile duct lumen and is regarded as a biliary counterpart of intraductal papillary mucinous neoplasm of the pancreas. IPNBs display a spectrum of premalignant lesion towards invasive cholangiocarcinoma. The most common radiologic findings for IPNB are bile duct dilatation and intraductal masses. The major treatment of IPNB is surgical resection. Ultrasonography, computed tomography, magnetic resonance image, and cholangiography are usually performed to assess tumor location and extension. Cholangioscopy can confirm the histology and assess the extent of the tumor including superficial spreading along the biliary epithelium. However, pathologic diagnosis by preoperative biopsy cannot always reflect the maximum degree of atypia, because IPNBs are often composed of varying degrees of cytoarchitectural atypia. IPNBs are microscopically classified into four epithelial subtypes, such as pancreatobiliary, intestinal, gastric, and oncocytic types. Most cases of IPNB are IPN with high-grade intraepithelial neoplasia or with an associated invasive carcinoma. The histologic types of invasive lesions are either tubular adenocarcinoma or mucinous carcinoma. Although several authors have investigated molecular genetic changes during the development and progression of IPNB, these are still poorly characterized and controversial. Masayuki Ohtsuka, Hiroaki Shimizu, Atsushi Kato, Hideyuki Yoshitomi, Katsunori Furukawa, Toshio Tsuyuguchi, Yuji Sakai, Osamu Yokosuka, and Masaru Miyazaki Copyright © 2014 Masayuki Ohtsuka et al. All rights reserved. New Insights into the Pathogenesis of Alcohol-Induced ER Stress and Liver Diseases Tue, 29 Apr 2014 09:33:13 +0000 Alcohol-induced liver disease increasingly contributes to human mortality worldwide. Alcohol-induced endoplasmic reticulum (ER) stress and disruption of cellular protein homeostasis have recently been established as a significant mechanism contributing to liver diseases. The alcohol-induced ER stress occurs not only in cultured hepatocytes but also  in vivo  in the livers of several species including mouse, rat, minipigs, zebrafish, and humans. Identified causes for the ER stress include acetaldehyde, oxidative stress, impaired one carbon metabolism, toxic lipid species, insulin resistance, disrupted calcium homeostasis, and aberrant epigenetic modifications. Importance of each of the causes in alcohol-induced liver injury depends on doses, duration and patterns of alcohol exposure, genetic disposition, environmental factors, cross-talks with other pathogenic pathways, and stages of liver disease. The ER stress may occur more or less all the time during alcohol consumption, which interferes with hepatic protein homeostasis, proliferation, and cell cycle progression promoting development of advanced liver diseases. Emerging evidence indicates that long-term alcohol consumption and ER stress may directly be involved in hepatocellular carcinogenesis (HCC). Dissecting ER stress signaling pathways leading to tumorigenesis will uncover potential therapeutic targets for intervention and treatment of human alcoholics with liver cancer. Cheng Ji Copyright © 2014 Cheng Ji. All rights reserved. Targeting Interleukin-4 Receptor Alpha by Hybrid Peptide for Novel Biliary Tract Cancer Therapy Sun, 27 Apr 2014 09:15:41 +0000 It is known that the interleukin-4 receptor α (IL-4Rα) is highly expressed on the surface of various human solid tumors. We previously designed novel IL-4Rα-lytic hybrid peptide composed of binding peptide to IL-4Rα and cell-lytic peptide and reported that the designed IL-4Rα-lytic hybrid peptide exhibited cytotoxic and antitumor activity both in vitro and in vivo against the human pancreatic cancer cells expressing IL-4Rα. Here, we evaluated the antitumor activity of the IL-4Rα-lytic hybrid peptide as a novel molecular targeted therapy for human biliary tract cancer (BTC). The IL-4Rα-lytic hybrid peptide showed cytotoxic activity in six BTC cell lines with a concentration that killed 50% of all cells (IC50) as low as 5 μM. We also showed that IL-4Rα-lytic hybrid peptide in combination with gemcitabine exhibited synergistic cytotoxic activity in vitro. In addition, intravenous administration of IL-4Rα-lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human BTC in vivo. Taken together, these results indicated that the IL-4Rα-lytic hybrid peptide is a potent agent that might provide a novel therapy for patients with BTC. Kahori Seto, Junichi Shoda, Tomohisa Horibe, Eiji Warabi, Masayuki Kohno, Toru Yanagawa, Hiroki Bukawa, Yasuni Nakanuma, and Koji Kawakami Copyright © 2014 Kahori Seto et al. All rights reserved. What Are the Precursor and Early Lesions of Peripheral Intrahepatic Cholangiocarcinoma? Tue, 22 Apr 2014 00:00:00 +0000 Cholangiocarcinoma (CC) is divided into distal, perihilar, and intrahepatic CCs (ICCS), and are further subdivided into large bile duct ICC and peripheral ICC. In distal and perihilar CC and large duct ICC, biliary intraepithelial neoplasm (BilIN) and intraductal papillary neoplasm (IPN) have been proposed as precursor lesions. Peripheral ICC, bile duct adenoma (BDA), biliary adenofibroma (BAF), and von Meyenburg complexes (VMCs) are reportedly followed by development of ICCs. Herein, we surveyed these candidate precursor lesions in the background liver of 37 cases of peripheral ICC and controls (perihilar CC, 34 cases; hepatocellular carcinoma, 34 cases and combined hepatocellular cholangiocarcinoma, 25 cases). In the background liver of peripheral ICC, BDA and BAF were not found, but there were not infrequently foci of BDA-like lesions and atypical bile duct lesions involving small bile ducts (32.4% and 10.8%, resp.). VMCs were equally found in peripheral CCs and also control CCs. In conclusion, BDA, BAF, and VMCs are a possible precursor lesion of a minority of peripheral CCs, and BDA-like lesions and atypical bile duct lesions involving small bile ducts may also be related to the development of peripheral ICC. Further pathologic studies on these lesions are warranted for analysis of development of peripheral ICCs. Yasuni Nakanuma, Akemi Tsutsui, Xiang Shan Ren, Kenichi Harada, Yasunori Sato, and Motoko Sasaki Copyright © 2014 Yasuni Nakanuma et al. All rights reserved. Histological Characterization of Biliary Intraepithelial Neoplasia with respect to Pancreatic Intraepithelial Neoplasia Thu, 10 Apr 2014 11:35:41 +0000 Biliary intraepithelial neoplasia (BilIN) is a precursor lesion of hilar/perihilar and extrahepatic cholangiocarcinoma. BilIN represents the process of multistep cholangiocarcinogenesis and is the biliary counterpart of pancreatic intraepithelial neoplasia (PanIN). This study was performed to clarify the histological characteristics of BilIN in relation to PanIN. Using paraffin-embedded tissue sections of surgically resected specimens of cholangiocarcinoma associated with BilIN and pancreatic ductal adenocarcinoma associated with PanIN, immunohistochemical staining was performed using primary antibodies against MUC1, MUC2, MUC5AC, cyclin D1, p21, p53, and S100P. For mucin staining, Alcian blue pH 2.5 was used. Most of the molecules examined here showed similar expression patterns in BilIN and PanIN, in which their expression tended to increase along with the increase in atypia of the epithelial lesions. Significant differences were observed in the increase in mucin production and the expression of S100P in PanIN-1 and the expression of p53 in PanIN-3, when compared with those in BilIN of a corresponding grade. These results suggest that cholangiocarcinoma and pancreatic ductal adenocarcinoma share, at least in part, a common carcinogenic process and further confirm that BilIN can be regarded as the biliary counterpart of PanIN. Yasunori Sato, Kenichi Harada, Motoko Sasaki, and Yasuni Nakanuma Copyright © 2014 Yasunori Sato et al. All rights reserved. The Association between Female Genital Cutting and Spousal HCV Infection in Egypt Thu, 20 Mar 2014 13:01:15 +0000 Objective. To identify the risk factors for HCV infection within married couples in Egypt. Methods. In 2008 Egypt conducted its first nationally representative survey of HCV prevalence. 11126 of the 12780 individuals aged 15–59 year who were sampled agreed to participate and provided information via a questionnaire about demographic and behavioural characteristics and blood for HCV antibody and RNA analysis. We assessed the risk factors for HCV infection in a subsample of 5182 married individuals via multivariate logistic regression. Results. Overall HCV antibody prevalence in the married couples was 18.2% (95% CI, 16.8–19.6). HCV antibody prevalence was higher in the husbands (23.7%) than the wives (12.1%; ). Having a spouse who was infected with HCV was an independent risk factor for HCV infection with odds ratios of 2.1 (95% CI, 1.6–2.9) and 2.2 (95% CI, 1.6–3.1) for women and men, respectively. Husbands whose wives had experienced female genital cutting (FGC) had a higher prevalence of HCV and this relationship was driven by a strong association in urban areas. Amongst the women there was no association between FGC and HCV overall but in urban areas only women who had experienced FGC were HCV infected. Conclusions. This study provides additional evidence of the importance of intrafamilial transmission of HCV in Egypt. Chris R. Kenyon and Robert Colebunders Copyright © 2014 Chris R. Kenyon and Robert Colebunders. All rights reserved. Patterns of Antimicrobial Resistance in the Causative Organisms of Spontaneous Bacterial Peritonitis: A Single Centre, Six-Year Experience of 1981 Samples Thu, 20 Mar 2014 07:56:07 +0000 Background/Aims. Spontaneous bacterial peritonitis (SBP) is one of the leading causes of morbidity and mortality in patients with cirrhosis. This study aims to determine the microbial agents of SBP and the pattern of antibiotic resistance, in a large number of ascitic samples. Methodology. In a cross-sectional, single center, hospital based study, 1981 consecutive ascitic fluid samples were recruited from 2005 to 2011. Samples were dichotomized into three-year periods, in order to assess the trend of resistance to the first-line empirical antibiotics. Results. SBP was found in 482 (24.33%) of samples, of which 314 (65.15%) were culture positive. The most prevalent isolated pathogen was E. coli (33.8%), followed by staphylococcus aureus (8.9%) and Enterococcus (8.6%). No significant changes in the proportion of gram-negative/gram-positive infections occurred during this period. A percentage of resistant strains to cefotaxime (62.5%, 85.7%), ceftazidim (73%, 82.1%), ciprofloxacin (30, 59.8%), ofloxacin (36.8%, 50%), and oxacilin (35%, 51.6%) were significantly increased. E. coli was most sensitive to imipenem, piperacillin-tazobactam, amikacin, ceftizoxime, and gentamicin. Conclusions. The microbial aetiology of SBP remains relatively constant. However, the resistance rate especially to the first-line recommended antibiotics was significantly increased. This pattern must be watched closely and taken into account in empirical antibiotic treatment. Sara Sheikhbahaei, Alireza Abdollahi, Nima Hafezi-Nejad, and Elham Zare Copyright © 2014 Sara Sheikhbahaei et al. All rights reserved. Effect of Platelet-Rich Plasma on CCl4-Induced Chronic Liver Injury in Male Rats Sun, 23 Feb 2014 11:43:01 +0000 Platelet-rich plasma (PRP) has been of great concern to the scientists and doctors who are involved in wound healing and regenerative medicine which focuses on repairing and replacing damaged cells and tissues. Growth factors of platelet-rich plasma are cost-effective, available, and is more stable than recombinant human growth factors. Given these valuable properties, we decided to assess the effect of PRP on -induced hepatotoxicity on rats. The rats received (1 mL/kg, i.p. 1 : 1 in olive oil) twice per week for 8 weeks. Five weeks after injection, the rats also received PRP (0.5 mL/kg, s.c.) two days a week for three weeks. Twenty-four hours after last injection, the animals bled and their livers dissected for biochemical and histopathological studies. Blood analysis was performed to evaluate enzyme activity. The results showed that PRP itself was not toxic for liver and could protect the liver from -induced histological damages and attenuated oxidative stress by increase in glutathione content and decrease in lipid peroxidative marker of liver tissue. The results of the present study lend support to our beliefs in hepatoprotective effects of PRP. Zahra Hesami, Akram Jamshidzadeh, Maryam Ayatollahi, Bita Geramizadeh, Omid Farshad, and Akbar Vahdati Copyright © 2014 Zahra Hesami et al. All rights reserved. Serum Cytokeratin-18 Is Associated with NOX2-Generated Oxidative Stress in Patients with Nonalcoholic Fatty Liver Wed, 29 Jan 2014 00:00:00 +0000 Background & Aims. Hepatocyte apoptosis may play a role in progression of nonalcoholic fatty liver and oxidative stress seems one of the key mechanisms responsible for liver damage. The aim was to determine the association of oxidative stress with cytokeratin-18 M30 fragment levels, a marker of hepatocyte apoptosis. Methods. Steatosis severity was defined according to Hamaguchi’s echographic criteria in 209 patients with nonalcoholic fatty liver. Serum cytokeratin-18, urinary 8-iso-prostaglandin F2α, soluble NOX2-derived peptide, and adiponectin were measured. Results. Serum cytokeratin-18 progressively increased with steatosis severity (from 169.5 (129.3/183.8) to 176 (140/190) and 180 (169.5/192.5) μIU/mL in mild, moderate, and severe steatosis, respectively; ). After stratification by cytokeratin-18 tertiles, a significant progression of body mass index, HOMA-IR, triglycerides, urinary 8-iso-PGF2α, soluble NOX2-derived peptide, and of the prevalence of diabetes and severe steatosis was found, while HDL-cholesterol and adiponectin progressively decreased. A positive correlation between cytokeratin-18 and body mass index, HOMA-IR, Hamaguchi’s score, urinary 8-iso-PGF2α, and soluble NOX2-derived peptide and a negative correlation between cytokeratin-18 and HDL-cholesterol and adiponectin were found. Body mass index, adiponectin, and soluble NOX2-derived peptide were independent predictors of serum cytokeratin-18 levels (adjusted ). Conclusion. We support an association between oxidative stress and severity of liver damage in patients with nonalcoholic fatty liver. M. Del Ben, L. Polimeni, F. Baratta, S. Bartimoccia, R. Carnevale, L. Loffredo, P. Pignatelli, F. Violi, and F. Angelico Copyright © 2014 M. Del Ben et al. All rights reserved. Quantification of Pregenomic RNA and Covalently Closed Circular DNA in Hepatitis B Virus-Related Hepatocellular Carcinoma Thu, 19 Dec 2013 09:08:07 +0000 Pregenomic RNA (pgRNA) is generated from covalently closed circular DNA (cccDNA) and plays important roles in viral genome amplification and replication. Hepatic pgRNA and cccDNA expression levels indicate viral persistence and replication activity. This study was aimed to measure hepatic pgRNA and cccDNA expression levels in various states of hepatitis B virus (HBV) infection. Thirty-eight hepatocellular carcinoma (HCC) patients, including 14 positive for hepatitis B surface antigen (HBsAg) and 24 negative for HBsAg but positive for anti-hepatitis B core (anti-HBc) antibody, were enrolled in this study. In HBsAg-negative but anti-HBc-positive group, HBV-DNA was detected in 20 of 24 (83%) noncancerous liver tissues for at least two genomic regions based on polymerase chain reaction (PCR) analysis. pgRNA and cccDNA expression levels in occult HBV-infected patients were significantly lower than those in HBsAg-positive patients (). pgRNA and cccDNA in cancerous tissues were also detected without significant difference from those in noncancerous tissues. In conclusion, cccDNA and pgRNA are detected and represented HBV replication not only in noncancerous but also in cancerous liver tissues. In addition, the replication is shown in not only patients with HBsAg-positive but also occult HBV-infected patients, suggesting the contribution to HCC development. Fugui Bai, Yoshihiko Yano, Takumi Fukumoto, Atsushi Takebe, Motofumi Tanaka, Kaori Kuramitsu, Nungki Anggorowati, Hanggoro Tri Rinonce, Dewiyani Indah Widasari, Masaya Saito, Hirotaka Hirano, Takanobu Hayakumo, Yasushi Seo, Takeshi Azuma, Yonson Ku, and Yoshitake Hayashi Copyright © 2013 Fugui Bai et al. All rights reserved. The Role of Bridging Therapy in Hepatocellular Carcinoma Thu, 19 Dec 2013 07:52:03 +0000 Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver accounting for 7% of all cancers worldwide. Most cases of HCC develop within an established background of chronic liver disease. For that reason, liver resection is only possible in selected patients. Liver transplantation has become the treatment of choice in patients with HCC, end-stage liver disease, and significant portal hypertension. Shortage of organ donors has resulted in overall increase of waiting list time with increased risk of dropout due to tumor progression. Neoadjuvant therapies have emerged as an alternative to control tumor growth in patients while waiting. The aim of this study is to review the literature on the role of bridging therapy and downstaging prior to liver transplantation in patients with HCC. We are also presenting our single-center experience of 96 patients undergoing transplantation for HCC with and without bridging therapy. Roberto Galuppo, Angie McCall, and Roberto Gedaly Copyright © 2013 Roberto Galuppo et al. All rights reserved. Diastolic Dysfunction and Severity of Cirrhosis in Nonalcoholic Cirrhotic Patients Tue, 26 Nov 2013 10:43:43 +0000 Background. In this study, we evaluated the association between diastolic dysfunction severity and severity of cirrhosis in nonalcoholic cirrhotic patients. Methods. This cross-sectional study was conducted on all nonalcoholic cirrhotic patients who were admitted in Rasht Razi hospital the Cancer of Guilan Province, north of Iran, from January 2011 to March 2012. Severity of cirrhosis was evaluated by Child-Pugh score. A 12-lead surface ECG and echocardiographic studies were performed. We used a HDI 3000 (Philips ATL, Bothell, WA, USA) equipped with 2 to 4 MHz probes. Diastolic function was determined by an expert cardiac sonographer. Data were analyzed by SPSS for win (version16). A value less than 0.05 was considered significant. Results. Sixty-tree percent of patients were male. The mean age of patients was years. 22%, 38%, and 40% of patients were considered as child class A, B, and C, respectively. There was a significant relation between diastolic dysfunction and disease duration (), female gender (), age > 60 years (), and severity of cirrhosis (). On multivariate analysis, decreased E/A ratio () and disease duration () showed an independent significant relation. Conclusion. According to the relation between severity of cirrhosis and diastolic dysfunction, we recommend cardiac assessment in all child B and C cirrhotic patients. A. Salari, A. Shafaghi, M. Ofoghi, A. Saeidinia, and F. Mansour-Ghanaei Copyright © 2013 A. Salari et al. All rights reserved. Role of FNA and Core Biopsy of Primary and Metastatic Liver Disease Thu, 21 Nov 2013 10:25:33 +0000 Objective. To examine our experience with cytology and histology biopsy of the liver and to define methods for improvement of diagnosis of primary liver tumors. Methods. This include retrospective study of 189 biopsies of 185 liver masses for cytological or histological analysis. Patients were subdivided into two groups. Group 1 consisted of 124 suspected metastasis. Group 2 consisted of 61 suspected primary neoplasms. Biopsies were considered positive or equivocal. In equivocal cases, special stains were performed. In Group 2, cases were classified by contrast CT or MRI as to (I) classic HCC, (II) infiltrated HCC, or (Ill) equivocal. Results. Definitive diagnosis was obtained in 117/124 masses (94%) in Group 1, 48/61 masses (79%) in Group 2, and (Ill) equivocal 13 cases in Group II. In two equivocal cases in which special stains were performed, they were reclassified as HCC. In 8/13 cases, CT findings were consistent with HCC. Conclusion. Liver biopsies are useful in obtaining a definitive diagnosis of suspected metastatic liver disease. Biopsy results are less reliable in patients with suspected primary liver tumors. In these situations, strategies can include basing treatment on imaging criteria or use of newer special pathological stains. Advances in Knowledge. Use of newer special immunological stains improves accuracy in definitive diagnosis of primary liver tumors. John P. McGahan, John Bishop, John Webb, Lydia Howell, Natalie Torok, Ramit Lamba, and Michael T. Corwin Copyright © 2013 John P. McGahan et al. All rights reserved. Metastatic Lesions to the Liver Sun, 17 Nov 2013 11:31:27 +0000 Jorge Ortiz, David K. Imagawa, Roberto Verzaro, Francesco Serafini, and Liise K. Kayler Copyright © 2013 Jorge Ortiz et al. All rights reserved. Impact of Pretransplant Hepatic Encephalopathy on Liver Posttransplantation Outcomes Wed, 13 Nov 2013 13:16:44 +0000 Patients with cirrhosis commonly experience hepatic encephalopathy (HE), a condition associated with alterations in behavior, cognitive function, consciousness, and neuromuscular function of varying severity. HE occurring before liver transplant can have a substantial negative impact on posttransplant outcomes, and preoperative history of HE may be a predictor of posttransplant neurologic complications. Even with resolution of previous episodes of overt or minimal HE, some patients continue to experience cognitive deficits after transplant. Because HE is one of the most frequent pretransplant complications, improving patient HE status before transplant may improve outcomes. Current pharmacologic therapies for HE, whether for the treatment of minimal or overt HE or for prevention of HE relapse, are primarily directed at reducing cerebral exposure to systemic levels of gut-derived toxins (e.g., ammonia). The current mainstays of HE therapy are nonabsorbable disaccharides and antibiotics. The various impacts of adverse effects (such as diarrhea, abdominal distention, and dehydration) on patient's health and nutritional status should be taken into consideration when deciding the most appropriate HE management strategy in patients awaiting liver transplant. This paper reviews the potential consequences of pretransplant HE on posttransplant outcomes and therapeutic strategies for the pretransplant management of HE. Lewis W. Teperman Copyright © 2013 Lewis W. Teperman. All rights reserved. Pretreatment of Small-for-Size Grafts In Vivo by γ-Aminobutyric Acid Receptor Regulation against Oxidative Stress-Induced Injury in Rat Split Orthotopic Liver Transplantation Tue, 08 Oct 2013 09:00:07 +0000 Background. Graft pretreatment to limit postoperative damage has the advantage of overcoming a current issue in liver transplantation (LT). The strategic potential of graft pretreatment in vivo by a specific agonist for γ-aminobutyric acid receptor (GABAR) was investigated in the rat LT model with a small-for-size graft (SFSG). Methods. Recipient rats were divided into three groups according to donor treatments and recipient surgeries: (i) saline and laparotomy, (ii) saline and split orthotopic liver transplantation (SOLT) with 40%-SFSG, and (iii) GABAR agonist and SOLT with 40%-SFSG. Survival was evaluated. Blood and liver samples were collected 6 h after surgery. Immunohistological assessment for apoptotic induction and western blotting for 4-hydroxynonenal, ataxia-telangiectasia mutated kinase (ATM), histone H2AX, phosphatidylinositol-3 kinase (PI3K), Akt, and free radical scavenging enzymes were performed. Results. Pretreatment by GABAR showed improvement in survival, histopathological assessment, and biochemical tests. Apoptotic induction and oxidative stress were observed after SOLT with an SFSG, and this damage was limited by GABAR regulation. GABAR regulation appeared to reduce DNA damage via the ATM/H2AX pathway and to promote cell survival via the PI3K/Akt pathway. Conclusions. Pretreatment in vivo by GABAR regulation improves graft damage after SOLT with an SFSG. This strategy may be advantageous in LT. Tomohide Hori, Shinji Uemoto, Lindsay B. Walden, Feng Chen, Ann-Marie T. Baine, Toshiyuki Hata, and Justin H. Nguyen Copyright © 2013 Tomohide Hori et al. All rights reserved. Implication for Bone Marrow Derived Stem Cells in Hepatocyte Regeneration after Orthotopic Liver Transplantation Tue, 10 Sep 2013 10:16:53 +0000 The liver has the outstanding ability to regenerate itself and restore parenchymal tissue after injury. The most common cell source in liver growth/regeneration is replication of preexisting hepatocytes although liver progenitor cells have been postulated to participate in liver regeneration in cases of massive injury. Bone marrow derived hematopoietic stem cells (BM-HSC) have the formal capacity to act as a source for hepatic regeneration under special circumstances; however, the impact of this process in liver tissue maintenance and regeneration remains controversial. Whether BM-HSC are involved in liver regeneration or not would be of particular interest as the cells have been suggested to be an alternative donor source for the treatment of liver failure. Data from murine models of liver disease show that BM-HSC can repopulate liver tissue and restore liver function; however, data obtained from human liver transplantation show only little evidence for liver regeneration by this mechanism. The cell source for liver regeneration seems to depend on the nature of regeneration process and the extent of injury; however, the precise mechanisms still need to be resolved. Current data suggest, that in human orthotopic liver transplantation, liver regeneration by BM-HSC is a rather rare event and therefore not of clinical relevance. N. Pilat, L. Unger, and G. A. Berlakovich Copyright © 2013 N. Pilat et al. All rights reserved. Etiologies and Outcomes of Acute Liver Failure in a Spanish Community Mon, 19 Aug 2013 10:44:57 +0000 Previous retrospective study (1992 to 2000) performed in Spain showed that drug toxicity, viral hepatitis, and indeterminate etiology were the most prevalent causes of acute liver failure (ALF). In the last decade, there is no information about ALF in our country. For these reasons we analyze retrospectively, in a ten-year period (2000 to 2010), the presumed causes, clinical characteristics, course, and outcome of ALF in a Spanish community. Causes of ALF were indeterminate in 4 patients (24%), acute hepatitis B infection in 4 patients (24%), drug or toxic reactions in 4 patients (24%), including one case of acetaminophen overdose, followed by miscellaneous causes. The overall short-term survival (6 weeks after admission) was 65%. Liver transplantation was performed in 11 patients with a survival of 82%. Despite fulfilling criteria, 2 patients were not transplanted because of contraindications; they both died. In summary, acute hepatitis B and indeterminate cause are still being the most frequent causes of ALF in our region, and patients with ALF have an excellent chance of survival after emergency liver transplantation. Acetaminophen overdose still represents a very rare cause of ALF in our community. Emilio Fábrega, Miguel Ángel Mieses, Alvaro Terán, Irene Moraleja, Fernando Casafont, Javier Crespo, and Fernando Pons-Romero Copyright © 2013 Emilio Fábrega et al. All rights reserved.