ISRN Hepatology The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Hepatic Encephalopathy: From the Pathogenesis to the New Treatments Wed, 04 Jun 2014 08:56:08 +0000 Hepatic encephalopathy is a frequent and serious complication of liver cirrhosis; the pathophysiology of this complication is not fully understood although great efforts have been made during the last years. There are few prospective studies on the epidemiology of this complication; however, it is known that it confers with high short-term mortality. Hepatic encephalopathy has been classified into different groups depending on the degree of hepatic dysfunction, the presence of portal-systemic shunts, and the number of episodes. Due to the large clinical spectra of overt EH and the complexity of cirrhotic patients, it is very difficult to perform quality clinical trials for assessing the efficacy of the treatments proposed. The physiopathology, clinical manifestation, and the treatment of HE is a challenge because of the multiple factors that converge and coexist in an episode of overt HE. Juan Cordoba Copyright © 2014 Juan Cordoba. All rights reserved. The Wide and Complex Field of NAFLD Biomarker Research: Trends Mon, 28 Apr 2014 11:36:11 +0000 Background. Nonalcoholic fatty liver disease is now acknowledged as a complex public health issue linked to sedentary lifestyle, obesity, and related disorders like type 2 diabetes and metabolic syndrome. Aims. We aimed to retrieve its trends out of the huge amount of published data. Therefore, we conducted an extensive literature search to identify possible biomarker and/or biomarker combinations by retrospectively assessing and evaluating common and novel biomarkers to predict progression and prognosis of obesity related liver diseases. Methodology. We analyzed finally 62 articles accounting for 157 cohorts and 45,288 subjects. Results. Despite the various approaches, most cohorts were considerably small and rarely comparable. Also, we found that the same standard parameters were measured rather than novel biomarkers. Diagnostics approaches appeared incomparable. Conclusions. Further collaborative investigations on harmonizing ways of data acquisition and identifying such biomarkers for clinical use are necessary to yield sufficient significant results of potential biomarkers. Erika Wichro, Tanja Macheiner, Jasmin Schmid, Barbara Kavsek, and Karine Sargsyan Copyright © 2014 Erika Wichro et al. All rights reserved. Application of Real-Time Tissue Elastography with a Low Frequency Convex Array Probe: A Noninvasive Approach to Differential Diagnosis of Liver Tumors Wed, 02 Apr 2014 00:00:00 +0000 To evaluate diagnostic performance of real-time tissue elastography (RTE) with a low frequency convex array probe for distinguishing benign from malignant hepatic tumors through trans-abdominal examination, elasticity images of 210 liver tumors were obtained by EUB-7500 (Hitachi Medical Systems and 3.5 MHz probe) and eventually 121 liver tumors were analyzed in the study. Elasticity images were classified into four types, from type a to d. Regarding type a or b as benign tumors and type c or d as malignant ones, sensitivity, specificity, and accuracy were calculated and the consistency between the findings of RTE and the pathohistological diagnosis was evaluated. The sensitivity, specificity, and accuracy were separately 97.2%, 88.0%, and 93.4% (). Moreover, there was a good consistency between the findings of RTE and the pathological diagnosis (kappa value 0.86). Among elasticity images of all the malignant tumors, the hepatocellular carcinomas (HCCs) mainly appeared in type c, and liver metastatic cancers in type d. Thus, RTE utilized as a novel noninvasive imaging examination method enables us to distinguish benign from malignant liver tumors. Moreover, it provides certain information for the differential diagnosis between HCCs and liver metastatic cancers. Juan Wang, Hong Ai, Long Guo, Lifang Tan, Huilin Gong, Wei Wei, and Litao Ruan Copyright © 2014 Juan Wang et al. All rights reserved. The Evolution of Transjugular Intrahepatic Portosystemic Shunt: Tips Tue, 18 Mar 2014 08:55:31 +0000 Since Richter’s description in the literature in 1989 of the first procedure on human patients, transjugular intrahepatic portosystemic shunt (TIPS) has been worldwide considered as a noninvasive technique to manage portal hypertension complications. TIPS succeeds in lowering the hepatic sinusoidal pressure and in increasing the circulatory flow, thus reducing sodium retention, ascites recurrence, and variceal bleeding. Required several revisions of the shunt TIPS can be performed in case of different conditions such as hepatorenal syndrome, hepatichydrothorax, portal vein thrombosis, and Budd-Chiari syndrome. Most of the previous studies on TIPS procedure were based on the use of bare stents and most patients chose TIPS 2-3 years after traditional treatment, thus making TIPS appear to be not superior to endoscopy in survival rates. Bare stents were associated with higher incidence of shunt failure and consequently patients required several revisions during the follow-up. With the introduction of a dedicated e-PTFE covered stent-graft, these problems were completely solved, No more reinterventions are required with a tremendous improvement of patient’s quality of life. One of the main drawbacks of the use of e-PTFE covered stent-graft is higher incidence of hepatic encephalopathy. In those cases refractory to the conventional medical therapy, a shunt reduction must be performed. Fabrizio Fanelli Copyright © 2014 Fabrizio Fanelli. All rights reserved. Liver Transplantation for Hepatocellular Carcinoma beyond Milan Criteria: Multidisciplinary Approach to Improve Outcome Tue, 04 Mar 2014 13:51:10 +0000 The implementation of the Milan criteria (MC) in 1996 has dramatically improved prognosis after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). Liver transplantation has, thereby, become the standard therapy for patients with “early-stage” HCC on liver cirrhosis. The MC were consequently adopted by United Network of Organ Sharing (UNOS) and Eurotransplant for prioritization of patients with HCC. Recent advancements in the knowledge about tumor biology, radiographic imaging techniques, locoregional interventional treatments, and immunosuppressive medications have raised a critical discussion, if the MC might be too restrictive and unjustified keeping away many patients from potentially curative LT. Numerous transplant groups have, therefore, increasingly focussed on a stepwise expansion of selection criteria, mainly based on tumor macromorphology, such as size and number of HCC nodules. Against the background of a dramatic shortage of donor organs, however, simple expansion of tumor macromorphology may not be appropriate to create a safe extended criteria system. In contrast, rather the implementation of reliable prognostic parameters of tumor biology into selection process prior to LT is mandatory. Furthermore, a multidisciplinary approach of pre-, peri-, and posttransplant modulating of the tumor and/or the patient has to be established for improving prognosis in this special subset of patients. A. Kornberg Copyright © 2014 A. Kornberg. All rights reserved. Tumor Hemodynamics and Hepatocarcinogenesis: Radio-Pathological Correlations and Outcomes of Carcinogenic Hepatocyte Nodules Tue, 04 Mar 2014 00:00:00 +0000 Tumor hemodynamics of carcinogenic hepatocytes nodules, that is, low grade dysplastic nodules, high grade dysplastic nodules, early hepatocellular carcinomas (HCCs), and progressed HCCs, change during multistep dedifferentiation of the nodules. Morphometric analyses of inflow vessels of these nodules indicate that the portal veins of carcinogenic hepatocyte nodules monotonically decrease whereas the arteries bitonically change, first decrease and then increase. Findings on imaging techniques depicting these changes in tumor blood inflows, especially intra-arterial contrast-enhanced computed tomography, closely related not only to the histological differentiation of the nodules but also to the outcomes of the nodules. Histological analyses of connections between the vessels within the tumors and those in the surrounding livers and findings on imaging techniques indicate that drainage vessels of HCC change from hepatic veins to hepatic sinusoids and then to portal veins during multistep hepatocarcinogenesis. Understanding of tumor hemodynamics through radio-pathological correlations will be helpful in drawing up therapeutic strategies for carcinogenic hepatocyte nodules arising in cirrhosis. Kazuhiko Ueda, Osamu Matsui, Azusa Kitao, Satoshi Kobayashi, Jun Nakayama, Shinich Miyagawa, and Masumi Kadoya Copyright © 2014 Kazuhiko Ueda et al. All rights reserved. Cholangiocarcinoma: Biology, Clinical Management, and Pharmacological Perspectives Sun, 16 Feb 2014 15:32:49 +0000 Cholangiocarcinoma (CCA), or tumor of the biliary tree, is a rare and heterogeneous group of malignancies associated with a very poor prognosis. Depending on their localization along the biliary tree, CCAs are classified as intrahepatic, perihilar, and distal, and these subtypes are now considered different entities that differ in tumor biology, the staging system, management, and prognosis. When diagnosed, an evaluation by a multidisciplinary team is essential; the team must decide on the best therapeutic option. Surgical resection of tumors with negative margins is the best option for all subtypes of CCA, although this is only achieved in less than 50% of cases. Five-year survival rates have increased in the recent past owing to improvements in imaging techniques, which permits resectability to be predicted more accurately, and in surgery. Chemotherapy and radiotherapy are relatively ineffective in treating nonoperable tumors and the resistance of CCA to these therapies is a major problem. Although the combination of gemcitabine plus platinum derivatives is the pharmacological treatment most widely used, to date there is no standard chemotherapy, and new combinations with targeted drugs are currently being tested in ongoing clinical trials. This review summarizes the biology, clinical management, and pharmacological perspectives of these complex tumors. Rocio I. R. Macias Copyright © 2014 Rocio I. R. Macias. All rights reserved. Improved Serum Alpha-Fetoprotein Levels after Iron Reduction Therapy in HCV Patients Mon, 10 Feb 2014 10:02:32 +0000 Background and Aims. To examine the changes in serum alpha-fetoprotein (AFP) levels after iron reduction by therapeutic phlebotomy in chronic hepatitis C patients. Methods. This retrospective study included 26 chronic hepatitis C patients. The patients were developed iron depletion by repeated therapeutic phlebotomies. Results. Iron reduction therapy significantly reduced the median level of serum AFP from 13 to 7 ng/mL, ALT from 96 to 50 IU/L, gamma-glutamyl transpeptidase (GGT) from 55 to 28 IU/L, and ferritin from 191 to 10 ng/mL ( for each). The rate of decline in the AFP level correlated positively only with that in GGT , although a spurious correlation was observed between the rates of decline for AFP and ALT. The AFP level normalized (<10 ng/mL) posttreatment in eight (50%) of 16 patients who had elevated pretreatment AFP levels. Normalized post-treatment ALT and GGT levels were seen in 12% (3 of 26) and 39% (7 of 18) of the patients, respectively. Multivariate analysis identified a post-treatment GGT level of <30 IU/L as an independent factor associated with post-treatment AFP normalization (odds ratio, 21; 95% confidence interval, 1.5–293; ). Conclusions. Iron reduction by therapeutic phlebotomy can reduce serum AFP and GGT levels in chronic hepatitis C patients. Hidenao Noritake, Yoshimasa Kobayashi, Yukimasa Ooba, Kensuke Kitsugi, Shin Shimoyama, Satoru Yamazaki, Takeshi Chida, Shinya Watanabe, Kazuhito Kawata, and Takafumi Suda Copyright © 2014 Hidenao Noritake et al. All rights reserved. Chylous Ascites: Evaluation and Management Mon, 03 Feb 2014 13:20:17 +0000 Chylous ascites refers to the accumulation of lipid-rich lymph in the peritoneal cavity due to disruption of the lymphatic system secondary to traumatic injury or obstruction. Worldwide, abdominal malignancy, cirrhosis, and tuberculosis are the commonest causes of CA in adults, the latter being most prevalent in developing countries, whereas congenital abnormalities of the lymphatic system and trauma are commonest in children. The presence of a milky, creamy appearing ascitic fluid with triglyceride content above 200 mg/dL is diagnostic, and, in the majority of cases, unless there is a strong suspicion of malignancy, further investigations are not required in patients with cirrhosis. If an underlying cause is identified, targeted therapy is possible, but most cases will be treated conservatively, with dietary support including high-protein and low-fat diets supplemented with medium-chain triglycerides, therapeutic paracentesis, total parenteral nutrition, and somatostatins. Rarely, resistant cases have been treated by transjugular intrahepatic portosystemic shunt, surgical exploration, or peritoneovenous shunt. Said A. Al-Busafi, Peter Ghali, Marc Deschênes, and Philip Wong Copyright © 2014 Said A. Al-Busafi et al. All rights reserved. Protective Effects of Guava Pulp on Cholestatic Liver Injury Sun, 17 Nov 2013 10:50:29 +0000 Background. Cholestatic liver injury is a leading cause of chronic liver diseases involved with oxidative stress changes and inflammation; thus, antioxidant and anti-inflammation compound-rich guava may play a pivotal role in protecting against the cholestatic liver damages. Our aims for this study are to determine whether guava pulp (GP) has protective effects on cholestatic liver injury-induced mouse model and on interleukin-6 (IL-6) mediated proliferation of QBC939 cholangiocarcinoma cell line. Methods. Mice were induced to cholestatic liver damage by left and median bile duct ligation (LMBDL) surgery and then treated with GP. Plasma and liver samples were collected for biochemical and pathological assays. 5-Bromo-2′-deoxyuridine (BrdU) assay and Western blots were used to detect proliferation and gene expression in QBC939 cells, respectively. Results. Compared with LMBDL only group, in GP-treated mice, the levels of alanine aminotransferase (ALT) and bilirubin decreased, biliary epithelial cell proliferation and liver fibrogenesis were suppressed, Src/MEK/ERK1/2/c-Myc pathway and expressions of transforming growth factor β1(TGF-β1), tissue inhibitor of metalloproteinases TIMP), and procollagen 1α1(COL1α1) were downregulated significantly. Moreover, the GP extract reduced IL-6-enhanced QBC939 cell proliferation, p-ERK, and c-Myc expression as well. Conclusions. GP may provide a new perspective for the treatment of cholestatic liver injury. Jian Peng, Chunyan Yue, Kai Qiu, Jie Chen, Maria-Angeles Aller, Kwang Suk Ko, and Heping Yang Copyright © 2013 Jian Peng et al. All rights reserved. Overexpression of Regulatory T Cells Type 1 (Tr1) Specific Markers in a Patient with HCV-Induced Hepatocellular Carcinoma Wed, 23 Oct 2013 13:40:50 +0000 Hepatitis C virus (HCV) is an important causative agent of liver disease, but factors that determine the resolution or progression of infection are poorly understood. In this study, we suggested that existence of immunosuppressive mechanisms, supported by regulatory T cells and especially the regulatory T cell 1 subset (Tr1), may explain the impaired immune response during infection and thus the fibrosis aggravation to hepatocellular carcinoma (HCC). Using quantitative real-time PCR, we investigated the intra-hepatic presence of Tr1 cells in biopsies from a genotype 1b infected patient followed for an 18-year period from cirrhosis to HCC. We described a significant increase of gene expression in particular for the cytokines IL-10, TGF-β, and their receptors that were perfectly correlated with an increased expression of the Tr1 specific markers (combined expression of CD4, CD18, and CD49b). This was strongly marked since the patient evolved in the pathology and could explain the failure of the treatment. In conclusion, evidence of regulatory T cell installation in the liver of chronically infected patient with cirrhosis and HCC suggests for the first time a key role for these cells in the course of HCV infection. Laurissa Ouaguia, Olivier Morales, Dhafer Mrizak, Khaldoun Ghazal, Emmanuel Boleslawski, Claude Auriault, Véronique Pancré, Yvan de Launoit, Filoména Conti, and Nadira Delhem Copyright © 2013 Laurissa Ouaguia et al. All rights reserved. Roles of Vitamin A Metabolism in the Development of Hepatic Insulin Resistance Mon, 30 Sep 2013 14:36:22 +0000 The increase in the number of people with obesity- and noninsulin-dependent diabetes mellitus has become a major public health concern. Insulin resistance is a common feature closely associated with human obesity and diabetes. Insulin regulates metabolism, at least in part, via the control of the expression of the hepatic genes involved in glucose and fatty acid metabolism. Insulin resistance is always associated with profound changes of the expression of hepatic genes for glucose and lipid metabolism. As an essential micronutrient, vitamin A (VA) is needed in a variety of physiological functions. The active metablite of VA, retinoic acid (RA), regulates the expression of genes through the activation of transcription factors bound to the RA-responsive elements in the promoters of RA-targeted genes. Recently, retinoids have been proposed to play roles in glucose and lipid metabolism and energy homeostasis. This paper summarizes the recent progresses in our understanding of VA metabolism in the liver and of the potential transcription factors mediating RA responses. These transcription factors are the retinoic acid receptor, the retinoid X receptor, the hepatocyte nuclear factor 4, the chicken ovalbumin upstream promoter-transcription factor II, and the peroxisome proliferator-activated receptor . This paper also summarizes the effects of VA status and RA treatments on the glucose and lipid metabolism in vivo and the effects of retinoid treatments on the expression of insulin-regulated genes involved in the glucose and fatty acid metabolism in the primary hepatocytes. I discuss the roles of RA production in the development of insulin resistance in hepatocytes and proposes a mechanism by which RA production may contribute to hepatic insulin resistance. Given the large amount of information and progresses regarding the physiological functions of VA, this paper mainly focuses on the findings in the liver and hepatocytes and only mentions the relative findings in other tissues and cells. Guoxun Chen Copyright © 2013 Guoxun Chen. All rights reserved. NT-proBNP Changes in Patients with Ascites during Large Volume Paracentesis Sun, 22 Sep 2013 16:54:08 +0000 Background. N-terminal probrain natriuretic peptide (NT-proBNP) is a hormone involved in the regulation of cardiovascular homeostasis. Changes in serum NT-proBNP during large volume paracentesis (LVP) in patients with ascites have never before been examined. Aims. To determine if significant changes in serum NT-proBNP occur in patients undergoing LVP and the associated clinical correlates in patients with cirrhosis. Method. A total of 45 patients with ascites were prospectively recruited. Serum NT-proBNP, biochemistry, and haemodynamics were determined at baseline and at key time points during and after paracentesis. Results. 34 patients were analysed; 19 had ascites due to cirrhosis and 15 from malignancy. In those with cirrhosis, NT-proBNP decreased by 77.3 pg/mL at 2 L of drainage and 94.3 pg/mL at the end of paracentesis, compared with an increase of 10.5 pg/mL and 77.2 pg/mL in cancer patients at the same time points ( and ). Only congestive cardiac failure (CCF) was an independent predictor of significant NT-proBNP changes at the end of drainage in cirrhotic patients (). There were no significant changes in haemodynamics or renal biochemistry for either group. Conclusion. Significant reductions in serum NT-proBNP during LVP occur in patients with cirrhosis but not malignancy, and only comorbid CCF appeared to predict such changes. Vi Nguyen, Rob Zielinski, Paul Harnett, Katherine Miller, Henry Chan, Nikitha Vootakuru, Priya Acharya, Montaha Khan, Oliver Gibbs, Sarika Gupta, Anjla Devi, Shani Phillips, Jacob George, and David van der Poorten Copyright © 2013 Vi Nguyen et al. All rights reserved. Serum Levels of Interleukin-6 and Interleukin-10 as Biomarkers for Hepatocellular Carcinoma in Egyptian Patients Sun, 15 Sep 2013 14:44:06 +0000 Interleukin-10 (IL-10) and interleukin-6 (IL-6) have been reported to be related to hepatocellular carcinoma (HCC) prognosis. This study aimed to investigate the clinical usefulness of serum levels of IL-6 and IL-10 as biomarkers for HCC among high-risk patients. Materials and Methods. 80 individuals were enrolled in this study; they were categorized into 4 groups: group 1 healthy individuals (NC) (), group 2 chronic hepatitis C virus (HCV) patients (), group 3 cirrhotic patients (LC) (), and HCC group (). Using ELISA technique serum levels of IL-6, IL-10, and alpha fetoprotein (AFP) were evaluated in all groups. Results. The mean serum levels of IL-6 were significantly higher in HCC than in LC, HCV, and NC groups (, , , and ), respectively (); also the serum levels of IL-10 were significantly higher in HCC compared with LC, HCV, and NC groups (, , , and ) (). We also found that the tumor size is correlated strongly with IL-6 and IL-10 levels (, ; , ), respectively. Conclusion. The combination of those markers may help to identify a group of HCC patients with low AFP. Mohamed S. Othman, Ahmed M. Aref, Amal A. Mohamed, and Wesam A. Ibrahim Copyright © 2013 Mohamed S. Othman et al. All rights reserved. Absence of Hepatitis B Resistance Mutants before Introduction of Oral Antiviral Therapy Thu, 12 Sep 2013 09:18:12 +0000 Introduction. The aim of this study was to assess whether hepatitis B virus drug resistant mutations antedated the widespread use of nucleos(t)ide analogues in treatment naïve patients. A number of reports have suggested that drug resistant mutants can be detected in apparently treatment naïve patients. Study. Fifty deidentified serum samples collected from 1986 to 1992 from patients with replicative chronic HBV infection at the University of Miami were genotyped and tested for resistance mutations using a line probe assay InnoLiPA HBV DR v2/v3. Serum HBV DNA was measured. All patients had documented chronic HBV infection with a detectable viral load, HBeAg seropositivity, and absence of HIV infection. Results. Of the 50 individuals included, 86% were male, mean age was 40 ± 12 years, and mostly genotype A. The mean HBV DNA was 126 pg/mL (range 6.4 to 557.0). No mutations were identified. Conclusions. The absence of drug induced mutations in these sera collected several years prior to the introduction of oral antiviral therapy suggests that these mutations do not occur in treatment naïve populations. Detection of drug resistance in an apparently treatment naïve subject suggests either unrecognized prior antiviral therapy or infection by an inoculum from a treatment experienced patient. Martin Moehlen, Maria De Medina, Mary Hill, Lennox Jeffers, Eugene R. Schiff, and Paul Martin Copyright © 2013 Martin Moehlen et al. All rights reserved. Selective Arterial Embolization of Liver Metastases from Gastrinomas: A Single-Centre Experience Mon, 29 Jul 2013 10:40:44 +0000 Background. Gastrinomas are rare functional neuroendocrine tumors causing the Zollinger-Ellison syndrome (ZES). At presentation, up to 25% of gastrinomas are metastasized, predominantly to the liver. Embolization of liver metastases might reduce symptoms of ZES although a postembolization syndrome can occur. In this study, the results of embolization are presented, and the literature results are described. Methods. From a prospective database of pancreatic neuroendocrine tumors, all patients with liver metastatic gastrinomas were selected if treated with arterial embolization. Primary outcome parameters were symptom reduction, complications, and response rate. The literature search was performed with these items. Results. Three patients were identified; two presented with synchronous liver metastases. All the three patients had symptoms of ZES before embolization. Postembolization syndrome occurred in two patients. Six months after embolization, all the 3 patients had a clinical and complete radiological response; a biochemical response was seen in 2/3 patients. From the literature, only a small number of gastrinoma patients treated with liver embolization for liver metastases were found, and similar results were described. Conclusion. Selective liver embolization is an effective and safe therapy for the treatment of liver metastatic gastrinomas in the reduction of ZES. Individual treatment strategies must be made for the optimal success rate. Anneke P. J. Jilesen, Heinz Josef Klümpen, Olivier R. C. Busch, T. M. van Gulik, Krijn P. van Lienden, Dirk J. Gouma, and Els J. M. Nieveen van Dijkum Copyright © 2013 Anneke P. J. Jilesen et al. All rights reserved. Gastrointestinal Bleeding in Cirrhotic Patients with Portal Hypertension Mon, 22 Jul 2013 14:12:45 +0000 Gastrointestinal bleeding related to portal hypertension is a serious complication in patients with liver cirrhosis. Most patients bleed from esophageal or gastric varices, but bleeding from ectopic varices or portal hypertensive gastropathy is also possible. The management of acute bleeding has changed over the last years. Patients are managed with a combination of endoscopic and pharmacologic treatment. The endoscopic treatment of choice for esophageal variceal bleeding is variceal band ligation. Bleeding from gastric varices is treated by injection with cyanoacrylate. Treatment with vasoactive drugs as well as antibiotic treatment is started before or at the time point of endoscopy. The first-line treatment for primary prophylaxis of esophageal variceal bleeding is nonselective beta blockers. Pharmacologic therapy is recommended for most patients; band ligation is an alternative in patients with contraindications for or intolerability of beta blockers. Treatment options for secondary prophylaxis include variceal band ligation, beta blockers, a combination of nitrates and beta blockers, and combination of band ligation and pharmacologic treatment. A clear superiority of one treatment over the other has not been shown. Bleeding from portal hypertensive gastropathy or ectopic varices is less common. Treatment options include beta blocker therapy, injection therapy, and interventional radiology. Erwin Biecker Copyright © 2013 Erwin Biecker. All rights reserved. In Vivo Effect of Arsenic Trioxide on Keap1-p62-Nrf2 Signaling Pathway in Mouse Liver: Expression of Antioxidant Responsive Element-Driven Genes Related to Glutathione Metabolism Wed, 10 Jul 2013 09:03:45 +0000 Arsenic is a Group I human carcinogen, and chronic arsenic exposure through drinking water is a major threat to human population. Liver is one of the major organs for the detoxification of arsenic. The present study was carried out in mice in vivo after arsenic treatment through drinking water at different doses and time of exposure. Arsenic toxicity is found to be mediated by reactive oxygen species. Nuclear factor (erythroid-2 related) factor 2 (Nrf2)/Keap1 (Kelch-like ECH-associated protein 1)/ARE (antioxidant response element)—driven target gene system protects cells against oxidative stress and maintains cellular oxidative homeostasis. Our result showed 0.4 ppm, 2 ppm, and 4 ppm arsenic trioxide treatment through drinking water for 30 days and 90 days induced damages in the liver of Swiss albino mice as evidenced by histopathology, disturbances in liver function, induction of heat shock protein 70, modulation of trace elements, alteration in reduced glutathione level, glutathione-s-transferase and catalase activity, malondialdehyde production, and induction of apoptosis. Cellular Nrf2 protein level and mRNA level increased in all treatment groups. Keap1 protein as well as mRNA level decreased concomitantly in arsenic treated mice. Our study clearly indicates the important role of Nrf2 in activating ARE driven genes related to GSH metabolic pathway and also the adaptive response mechanisms in arsenic induced hepatotoxicity. Ritu Srivastava, Archya Sengupta, Sandip Mukherjee, Sarmishtha Chatterjee, Muthammal Sudarshan, Anindita Chakraborty, Shelley Bhattacharya, and Ansuman Chattopadhyay Copyright © 2013 Ritu Srivastava et al. All rights reserved. Female Genital Cutting and Hepatitis C Spread in Egypt Tue, 07 May 2013 11:49:46 +0000 A recent analysis of Egypt’s first nationally representative survey of hepatitis C virus (HCV) infection found female genital cutting (FGC) to be an independent risk factor for HCV infection for women in urban areas. We use the same dataset to extend this analysis. In an ecological analysis, we find a strong association between FGC and HCV prevalence (Pearson —74%;  ). HCV prevalence is significantly higher if FGC is performed by a non-Doctor (15.4%) than a Doctor (4.2%; ), and the calculated population attributable fraction of FGC for prevalent HCV seropositivity is high in women (79.8%). Chris Kenyon, Jozefien Buyze, Ludwig Apers, and Robert Colebunders Copyright © 2013 Chris Kenyon et al. All rights reserved. Metabolic Bone Disease in Viral Cirrhosis: A Prospective Study Sun, 21 Apr 2013 10:32:43 +0000 Background/Aim. Metabolic Bone disorders are well-recognized extrahepatic complications of cirrhosis. The aim was to report their prevalence and the associated factors to their development in patients with viral cirrhosis. Patients and Methods. All consecutive patients with viral cirrhosis were prospectively enrolled. Parathyroid hormone, 25-hydroxyvitamin D, liver function, and phosphocalcic tests were measured in all patients. Bone mineral density was measured at the lumbar spine and total hip by dual-energy X-ray absorptiometry. Data were analyzed using SPSS software. Results. Forty-six cirrhotic patients were included with hepatitis C (87%) and hepatitis B (13%). The Child-Pugh score was grade A in 87% of cases and grade B in 13%. Thirty-seven patients had decreased bone mineral density with osteopenia in 24 patients and osteoporosis in 13 patients. Decreased 25-hydroxyvitamin D was found in 95.6% of cases. Bone disorders were significantly more frequent in old patients with low body mass index, long duration of liver disease, and low 25-hydroxyvitamin D level. None of these factors was an independent factor associated with bone disorders. Conclusion. Our study revealed a high prevalence of metabolic bone disorders among viral cirrhotic patients. Consequently, bone mineral density assessment should be performed systematically in all cirrhotic patients. Rabia Goubraim, Nawal Kabbaj, Mouna Salihoun, Zakia Chaoui, M'Hamed Nya, and Naima Amrani Copyright © 2013 Rabia Goubraim et al. All rights reserved. Establishment and Validation of an Orthotopic Metastatic Mouse Model of Colorectal Cancer Sun, 21 Apr 2013 09:22:43 +0000 Metastases are largely responsible for cancer deaths in solid tumors due to the lack of effective therapies against disseminated disease, and there is an urgent need to fill this gap. This study demonstrates an orthotopic colorectal cancer (CRC) mouse model system to develop spontaneous metastasis in vivo and compare its reproducibility against human CRC. IGF1R-dependent GEO human CRC cells were used to study metastatic colonization using orthotopic transplantation procedures and demonstrated robust liver metastasis. Cell proliferation assays were performed both in the orthotopic primary colon and liver metastatic tumors, and human CRC patient’s specimen and similar patterns in H&E and Ki67 staining were observed between the orthotopically generated primary and liver metastatic tumors and human CRC specimens. Microarray analysis was performed to generate gene signatures, compared with deposited human CRC gene expression data sets, analyzed by Oncomine, and revealed similarity in gene signatures with increased aggressive markers expression associated with CRC in orthotopically generated liver metastasis. Thus, we have developed an orthotopic mouse model that reproduces human CRC metastasis. This model system can be effective in developing new therapeutic strategies against disseminated disease and could be implemented for identifying genes that regulate the development and/or maintenance of established metastasis. Ashwani Rajput, Ekta Agarwal, Premila Leiphrakpam, Michael G. Brattain, and Sanjib Chowdhury Copyright © 2013 Ashwani Rajput et al. All rights reserved. Mild Hypertransaminasemia in Primary Care Wed, 10 Apr 2013 09:40:26 +0000 The liver enzymes, alanine transaminase (ALT) or aspartate transaminase (AST), are commonly used in clinical practice as screening as well as diagnostic tests for liver diseases. ALT is more specific for liver injury than AST and has been shown to be a good predictor of liver related and all-cause mortality. Asymptomatic mild hypertransaminasemia (i.e., less than five times normal) is a common finding in primary care and this could be attributed to serious underlying condition or has transient and benign cause. Unfortunately, there are no good literatures available on the cost-effectiveness of evaluating patients with asymptomatic mild hypertransaminasemia. However, if the history and physical examination do not suggest a clear cause, a stepwise approach should be initiated based on pretest probability of the underlying liver disease. Nonalcoholic fatty liver disease is becoming the most common cause of mild hypertransaminasemia worldwide. Other causes include alcohol abuse, medications, and hepatitis B and C. Less common causes include hemochromatosis, α1-antitrypsin deficiency, autoimmune hepatitis, and Wilson's disease. Nonhepatic causes such as celiac disease, thyroid, and muscle disorders should be considered in the differential diagnosis. Referral to a specialist and a possible liver biopsy should be considered if persistent hypertransaminasemia for six months or more of unclear etiology. Said A. Al-Busafi and Nir Hilzenrat Copyright © 2013 Said A. Al-Busafi and Nir Hilzenrat. All rights reserved. Familial Budd-Chiari Syndrome in China: A Systematic Review of the Literature Thu, 28 Feb 2013 09:32:47 +0000 Familial occurrence of Budd-Chiari syndrome (BCS) has been reported in scattered cases, which potentially favors the congenital theory. A review of the literature was conducted to demonstrate this phenomenon in China. PubMed, VIP, and CNKI databases were searched for studies describing at least two Chinese BCS patients from the same one family. In the 18 eligible papers, 30 siblings or first-degree relatives from 14 families were diagnosed with BCS at 9 different centers. Common clinical presentations included varices of abdominal wall and lower limbs, edema of legs, and ascites. Type and location of obstruction were similar among these patients from the same one family. Screening for BCS was conducted in 65 family members from 3 families, demonstrating that 2 asymptomatic siblings from one family were further diagnosed with BCS. Factor V Leiden mutation was found in 3 of 4 patients from one family and in one of 2 patients from another one family. Prothrombin G20210A gene mutation was found in none of the 4 patients from the 2 families. In conclusion, our study showed the possibility of familial aggregation in Chinese BCS patients, but these available data cannot support the previous hypothesis that familial BCS originates from congenital vascular malformation. Xingshun Qi, Juan Wang, Weirong Ren, Ming Bai, Man Yang, Guohong Han, and Daiming Fan Copyright © 2013 Xingshun Qi et al. All rights reserved. The Treatment of Liver Metastases in Patients with Neuroendocrine Tumors in 2012 Thu, 14 Feb 2013 14:15:15 +0000 Neuroendocrine tumors (NETs) comprise a heterogeneous group of tumors that form a distinct entity. Approximately 75–80% of patients present with liver metastases at the time of their diagnosis, and 20%–25% will develop these lesions in the course of their disease. The presence of secondary deposits in the liver significantly increases the morbidity and mortality in these patients. The only potentially curative treatment is the surgical resection of the primary tumor and hepatic lesions. However, only 10% of patients presents under ideal conditions for that approach. Several techniques aimed at localized liver lesions have been applied also with interesting results in terms of survival and symptom control. The same has been demonstrated with new systemic therapies (target therapies). However, these are still under study, in order to define their true role in the management of these patients. This paper intends to address, in a general way, the various treatment options in patients with liver metastases from neuroendocrine tumors. Daniela Macedo, Teresa Amaral, Isabel Fernandes, Ana Rita Sousa, Ana Lúcia Costa, Isabel Távora, António Quintela, Paulo Cortes, and Luís Costa Copyright © 2013 Daniela Macedo et al. All rights reserved. Pathophysiological Significance of Hepatic Apoptosis Sun, 30 Dec 2012 14:20:36 +0000 Apoptosis is a classical pathological feature in liver diseases caused by various etiological factors such as drugs, viruses, alcohol, and cholestasis. Hepatic apoptosis and its deleterious effects exacerbate liver function as well as involvement in fibrosis/cirrhosis and carcinogenesis. An imbalance between apoptotic and antiapoptotic capabilities is a prominent characteristic of liver injury. The regulation of apoptosis and antiapoptosis can be a pivotal step in the treatment of liver diseases. Kewei Wang and Bingliang Lin Copyright © 2013 Kewei Wang and Bingliang Lin. All rights reserved. Predictors of Developing Hepatocellular Carcinoma in Treated HCV-Carriers in Morocco according to University Hospital Experience Sun, 23 Dec 2012 12:47:38 +0000 Introduction. Hepatitis C is the first major cause for HCC in Morocco. Antiviral treatment reduces the risk of developing HCC but few cases of HCC in HCV-treated patients were reported. We aimed to define this population’s features and to identify predictive factors of developing HCC. Patients and Methods. We included all HCV carriers who developed HCC after antiviral treatment from January 2002 to April 2010. We compare HCV-treated patients with no developed HCC to HCC population using khi-2 and Fisher Exact analysis. Results. 369 HVC-treated patients were considered, and 20 HCC were reported. The risk of HCC was not significant according to gender and genotypes (resp., and ). Advanced age and severe fibrosis were significant risk factors (resp., and ). HCC was reported in 2.6% of sustained virological responders versus 12.5% of nonresponders (). Conclusion. In our series, 5% of previously treated patients developed an HCC. Advanced age and severe fibrosis at HCV diagnosis are predictive factors of HCC occurrence. Sustained virological response reduces considerably the risk of HCC occurrence but screening is indicated even after SVR. Younès Cherradi, Rajaa Afifi, Hanaa Benbrahim, Wafaa Essamri, Imane Benelbarhdadi, Fatima Zahra Ajana, Hadj Omar El Malki, Mustapha Benazzouz, and Abdellah Essaid Copyright © 2013 Younès Cherradi et al. All rights reserved. Murine Models of Nonalcoholic Fatty Liver Disease and Steatohepatitis Wed, 12 Dec 2012 13:58:56 +0000 In 1980, Ludwig et al. first reported patients of steatohepatitis who lacked a history of excessive alcohol consumption but showed liver histology resembling alcoholic hepatitis and progression to cirrhosis of the liver accompanied by inflammation and fibrosis. The development of nonalcoholic steatohepatitis (NASH) is associated with obesity, diabetes mellitus, insulin resistance, and hyperlipidemia. However, the pathogenesis of NASH remains incomplete. A “multiple-hit” hypothesis for the pathogenesis of NASH based on an animal model has been proposed and remains a foundation for research in this field. We review the important dietary and genetic animal models and discuss the pathogenesis of NASH. Masashi Ninomiya, Yasuteru Kondo, and Tooru Shimosegawa Copyright © 2013 Masashi Ninomiya et al. All rights reserved. The Role of Interventional Radiology in Treating Complications following Liver Transplantation Mon, 03 Dec 2012 08:45:43 +0000 Liver transplantation (LT) is used to treat both adult and pediatric patients with end-stage liver disease or acute liver failure. It has become more prevalent as both the surgical technique and postoperative care have improved resulting in a reduced morbidity and mortality. As a result, there are more patients surviving longer after liver transplantation. Despite this, there remain serious complications from the procedure that have a significant outcome on the patient and may result in retransplantation. At the same time, there have been significant advances in the field of interventional radiology both in terms of technology and how these apply to the patients. In this paper, we review the commonest complications, diagnostic tests, and interventional management options available. Homoyoon Mehrzad and Kamarjit Mangat Copyright © 2013 Homoyoon Mehrzad and Kamarjit Mangat. All rights reserved. Quantifying Serum Level of Glycochenodeoxycholic Acid Using High Performance Liquid Chromatography in Obstructive Jaundice Patients Mon, 05 Nov 2012 11:25:38 +0000 Introduction. Accumulation of glycochenodeoxycholic acid (GCDC) in serum has a clinical significance as an inductor of pathological hepatocyte apoptosis, which impairs liver function. Inhibition of GCDC accumulation can be used as a marker in therapy. This study was aimed to quantify the serum level of GCDC in obstructive jaundice patients. Methodology. GCDC acid level in the serum was quantified using high performance liquid chromatography (HPLC) technique according to Muraca and Ghoos modified method. It was performed before and after decompression at day 7 and day 14. The sample was extracted with solid phase extraction (SPE) technique on SPE column. The results were analyzed using SPSS V 16.0 () and quantified with standard curve on GCDC acid. Result. There were 21 cases with range of GCDC acid serum level before decompression was 90.9 (SD 205.5) μmol/L and day 7 after decompression decreased to 4.0 (SD 46.4) μmol/L and then increased to 11.3 (SD 21.9) μmol/L (). This method could separate GCDC acid on serum with good resolution, high precision and accuracy, and linear calibration curve on measured level range. Conclusion. HPLC can quantify GCDC acid serum on obstructive jaundice patients and can be used to support its pharmacokinetic study. Toar J. M. Lalisang, Metta Sinta Sari Wiria, Vivian Sutikno, Melva Louisa, and Arie Estuningtyas Copyright © 2013 Toar J. M. Lalisang et al. All rights reserved.