International Journal of Hepatology The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . 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. Liver Injury Induced by Anticancer Chemotherapy and Radiation Therapy Wed, 17 Jul 2013 09:33:58 +0000 Cytotoxic chemotherapy prolongs survival of patients with advanced and metastatic tumors. This is, however, a double-edged sword with many adverse effects. Since the liver has a rich blood supply and plays an active role in the metabolism of medications, it is not surprising that there can be hepatic injury related to chemotherapy. In addition, radioembolization may affect the parenchyma of normal and cirrhotic livers. We review chemotherapy-associated liver injury in patients with colorectal liver metastases, including downsizing chemotherapy and neoadjuvant chemotherapy. We discuss the mechanism of the hepatic injury, secondary to reactive oxygen species, and the spectrum of hepatic injury including, steatosis, steatohepatitis, hepatic sinusoidal injury and highlight the pharmacogenomics of such liver insults. Methods for reducing and treating the hepatotoxicity are discussed for specific agents including tamxifen and the newly introduced targeted antibodies. Y. Maor and S. Malnick Copyright © 2013 Y. Maor and S. Malnick. All rights reserved. Management of Bleeding in Extrahepatic Portal Venous Obstruction Tue, 25 Jun 2013 18:32:56 +0000 Extrahepatic portal venous obstruction, although rare in the western world, is a common cause of major and life threatening upper gastrointestinal bleeding among the poor in developing countries. Patients have large spleens and stunted growth. The diagnosis is easily confirmed by Doppler ultrasonography. Endoscopy sclerotherapy is the best option for the control of acute variceal bleeding. For secondary prophylaxis of bleeding, the choice lies between repeated sclerotherapy and a portosystemic shunt. We believe that due consideration should be given to performing a splenectomy and a lienorenal shunt. Performed by experienced surgeons, it carries a low operative mortality of 1%, a rebleeding rate of about 10%, removes the large spleen, reverses hypersplenism, and is not followed by portosystemic encephalopathy. Most importantly, it is a onetime procedure particularly suited to those who have little access to blood transfusion and sophisticated medical facilities. N. Chaudhary, S. Mehrotra, M. Srivastava, and S. Nundy Copyright © 2013 N. Chaudhary et al. All rights reserved. Demonstration of Hepatitis C Virus RNA with In Situ Hybridization Employing a Locked Nucleic Acid Probe in Humanized Liver of Infected Chimeric Mice and in Needle-Biopsied Human Liver Tue, 18 Jun 2013 13:04:09 +0000 Background. In situ hybridization (ISH) with high sensitivity has been requested to demonstrate hepatitis C virus (HCV) RNA in formalin-fixed, paraffin-embedded (FFPE) sections of the liver. Methods. ISH employing a locked-nucleic-acid- (LNA-)modified oligonucleotide probe and biotin-free catalyzed signal amplification system (CSAII) was applied to HCV-RNA detection in the liver tissue. Nested reverse-transcription polymerase chain reaction (RT-PCR) was performed for HCV genotyping using total RNA extracted from FFPE sections. The target tissues included FFPE tissue sections of humanized livers in HCV-infected chimeric mice (HCV genotypes 1a, 1b, and 2a and noninfected) and of needle-biopsied livers from HCV-infected patients. Results. HCV-RNA was demonstrated with the ISH technique in HCV-infected liver tissues from both chimeric mice and 9 (82%) of 11 patients with HCV infection. The HCV signals were sensitive to RNase. Nested RT-PCR confirmed the genotype in 8 (73%) of 11 livers (type 1b: 6 lesions and type 2a: 2 lesions). HCV-RNA was not identified in chronic hepatitis B lesions, fatty liver, autoimmune hepatitis, and hepatocellular carcinoma. Conclusion. ISH using the LNA-modified oligonucleotide probe and CSAII was applicable to detecting HCV-RNA in routinely prepared FFPE liver specimens. Kazuya Shiogama, Ken-ichi Inada, Michinori Kohara, Hidemi Teramoto, Yasuyoshi Mizutani, Takanori Onouchi, and Yutaka Tsutsumi Copyright © 2013 Kazuya Shiogama et al. All rights reserved. Giant Hepatic Cyst with Septal Structure: Diagnosis and Management Wed, 29 May 2013 16:46:55 +0000 The hepatic cyst is a common benign liver tumor, and no surgical treatment is necessary. However, it is difficult to correctly diagnose the giant hepatic cyst containing the solid septal structures inside, from the malignant cystadenocarcinomas. The various imaging modalities such as computed tomography, magnetic resonance imaging, and ultrasonography, have been developed and are useful for the diagnosis of these liver tumors. Reviewing the other reports in this paper, the combination of more than 2 modalities will help to diagnose these tumors; however, the malignant potential is unable to be excluded if the tumor is huge. Therefore, the surgical resection should be considered for the huge hepatic cysts with septal structures if the correct diagnosis is unable to be made. For example, when the hemorrhages cause the granulation in the septa which often shows neovascularization, the imaging modalities are unable to define this situation from the malignant tissue with hypervascularity. Therefore, with the careful review of other reports, we conclude that if the imaging studies show the possible malignant potential or the sizing-up is marked, the surgical treatment should be considered with the consent from the patients. Toshihiro Sato, Michitaka Imai, Kazunao Hayashi, Osamu Isokawa, Tatsuya Nomura, Yoshiaki Tsuchiya, and Takashi Kawasaki Copyright © 2013 Toshihiro Sato et al. All rights reserved. Benign Hepatocellular Tumors: A Multidisciplinary Approach Tue, 28 May 2013 10:24:40 +0000 Paulette Bioulac-Sage, Luigi Grazioli, Türkan Terkivatan, and Charissa Chang Copyright © 2013 Paulette Bioulac-Sage et al. All rights reserved. Diagnosis and Management of Giant Hepatic Hemangioma: The Usefulness of Contrast-Enhanced Ultrasonography Thu, 16 May 2013 10:20:57 +0000 Giant hepatic hemangiomas, though often asymptomatic, may require intervention if rapid growth occurs. The imaging studies including the computed tomography, magnetic resonance imaging, and ultrasonography, and so on are effective for the diagnosis and the management of this tumor; however, due to its size and various patterns of these studies, we need to carefully consider the therapeutic methods. Compared to the cost needed for these modalities, recently developed and approved Perflubutane- (Sonazoid-) based contrast agent enhanced ultrasonography is reasonable and safe. The major advantage is the real-time observation of the vascular structure and function of the Kupffer cells. By this procedure, we can carefully follow the tumor growth or character change in a hemangioma and decide the timing of therapeutic intervention, since abdominal pain, abdominal mass, consumptive coagulopathy, and hemangioma growth are the signs for the therapeutic intervention. We reviewed recent reports about Sonazoid-based enhancement and also showed the representative images collected in our department. This is the first review showing the detailed findings of the giant hemangiomas using Perflubutane (Sonazoid). This review will help the physician in making the decision, and we hope that Sonazoid will gain widespread acceptance in the near future. Masaki Maruyama, Osamu Isokawa, Koki Hoshiyama, Ayako Hoshiyama, Mari Hoshiyama, and Yoshihiro Hoshiyama Copyright © 2013 Masaki Maruyama et al. All rights reserved. HBV Perinatal Transmission Mon, 22 Apr 2013 14:15:32 +0000 Hepatitis B is a serious public health problem all around the world. It is a blood-borne and sexually transmitted DNA virus in adults, but mother to child transmission of hepatitis B virus also occurs in infants born to hepatitis B surface antigen positive mothers. Muhammad Umar, Hamama-tul-Bushra, Shifa Umar, and Haider Ali Khan Copyright © 2013 Muhammad Umar et al. All rights reserved. Pathological Diagnosis of Hepatocellular Cellular Adenoma according to the Clinical Context Thu, 18 Apr 2013 12:12:51 +0000 In Europe and North America, hepatocellular adenomas (HCA) occur, classically, in middle-aged woman taking oral contraceptives. Twenty percent of women, however, are not exposed to oral contraceptives; HCA can more rarely occur in men, children, and women over 65 years. HCA have been observed in many pathological conditions such as glycogenosis, familial adenomatous polyposis, MODY3, after male hormone administration, and in vascular diseases. Obesity is frequent particularly in inflammatory HCA. The background liver is often normal, but steatosis is a frequent finding particularly in inflammatory HCA. The diagnosis of HCA is more difficult when the background liver is fibrotic, notably in vascular diseases. HCA can be solitary, or multiple or in great number (adenomatosis). When nodules are multiple, they are usually of the same subtype. HNF1α-inactivated HCA occur almost exclusively in woman. The most important point of the classification is the identification of β-catenin mutated HCA, a strong argument to identify patients at risk of malignant transformation. Some HCA already present criteria indicating malignant transformation. When the whole nodule is a hepatocellular carcinoma, it is extremely difficult to prove that it is the consequence of a former HCA. It is occasionally difficult to identify HCA remodeled by necrosis or hemorrhage. Paulette Bioulac-Sage, Christine Sempoux, Laurent Possenti, Nora Frulio, Hervé Laumonier, Christophe Laurent, Laurence Chiche, Jean Frédéric Blanc, Jean Saric, Hervé Trillaud, Brigitte Le Bail, and Charles Balabaud Copyright © 2013 Paulette Bioulac-Sage et al. All rights reserved. Modern Prospection for Hepatic Arterial Infusion Chemotherapy in Malignancies with Liver Metastases Wed, 17 Apr 2013 18:12:16 +0000 Malignancy with liver metastasis plays an important role in daily oncology practice, especially for primary cancers of the gastrointestinal tract and hepatopancreatobiliary system. On account of the dual vascular supply system and the fact that most metastatic liver tumors are supplied by the hepatic artery, hepatic artery infusion chemotherapy (HAIC) is an appealing method for the treatment of liver metastases. Herein, we summarize recent study results reported in the literature regarding the use of HAIC for metastatic liver tumors, with special focus on colorectal cancer. Yi-Hsin Liang, Yu-Yun Shao, Jia-Yi Chen, Po-Chin Liang, Ann-Lii Cheng, and Zhong-Zhe Lin Copyright © 2013 Yi-Hsin Liang et al. All rights reserved. Focal Nodular Hyperplasia and Hepatocellular Adenoma around the World Viewed through the Scope of the Immunopathological Classification Sun, 14 Apr 2013 14:07:10 +0000 Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) are benign hepatocellular tumors. The risk of bleeding and malignant transformation of HCA are strong arguments to differentiate HCA from FNH. Despite great progress that has been made in the differential radiological diagnosis of the 2 types of nodules, liver biopsy is sometimes necessary to separate the 2 entities. Identification of HCA subtypes using immunohistochemical techniques, namely, HNF1A-inactivated HCA (35–40%), inflammatory HCA (IHCA), and beta-catenin-mutated inflammatory HCA (b-IHCA) (50–55%), beta-catenin-activated HCA (5–10%), and unclassified HCA (10%) has greatly improved the diagnostic accuracy of benign hepatocellular nodules. If HCA malignant transformation occurs in all HCA subgroups, the risk is by far the highest in the β-catenin-mutated subgroups (b-HCA, b-IHCA). In the coming decade the management of HCA will be more dependent on the identification of HCA subtypes, particularly for smaller nodules (<5 cm) in terms of imaging, follow-up, and resection. Charles Balabaud, Wesal R. Al-Rabih, Pei-Jer Chen, Kimberley Evason, Linda Ferrell, Juan C. Hernandez-Prera, Shiu-Feng Huang, Thomas Longerich, Young Nyun Park, Alberto Quaglia, Peter Schirmacher, Christine Sempoux, Swan N. Thung, Michael Torbenson, Aileen Wee, Matthew M. Yeh, Shiou-Hwei Yeh, Brigitte Le Bail, Jessica Zucman-Rossi, and Paulette Bioulac-Sage Copyright © 2013 Charles Balabaud et al. All rights reserved. Gd-EOB-DTPA-Enhanced MRI for Detection of Liver Metastases from Colorectal Cancer: A Surgeon’s Perspective! Tue, 09 Apr 2013 12:13:44 +0000 Colorectal cancer affects over one million people worldwide annually, with the liver being the most common site of metastatic spread. Adequate resection of hepatic metastases is the only chance for a cure in a subset of patients, and five-year survival increases to 35% with complete resection. Traditionally, computed tomographic imaging (CT) was utilized for staging and to evaluate metastases in the liver. Recently, the introduction of hepatobiliary contrast-enhanced magnetic resonance imaging (MRI) agents including gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Eovist in the United States, Primovist in Europe, or Gd-EOB-DTPA) has proved to be a sensitive method for detection of hepatic metastases. Accurate detection of liver metastases is critical for staging of colorectal cancer as well as preoperative planning. Kelly J. Lafaro, Panayota Roumanis, Aram N. Demirjian, Chandana Lall, and David K. Imagawa Copyright © 2013 Kelly J. Lafaro et al. All rights reserved. Pathogenic Role of Iron Deposition in Reticuloendothelial Cells during the Development of Chronic Hepatitis C Thu, 04 Apr 2013 08:18:52 +0000 Aim. Chronic hepatitis C (CHepC) is frequently associated with hepatic iron overload, yet mechanisms underlying iron-induced liver injury have not been elucidated. We examined the significance of iron deposition in hepatocytes (HC) and reticuloendothelial cells (REC) in CHepC. Methods. Stainable hepatic iron was scored according to the iron deposition pattern in 373 patients. The levels of serum soluble TNF-α receptor (sTNFR2) and hepatic hepcidin mRNA and the efficacy of phlebotomy were compared among patients with different iron deposition patterns. Results. Serum transaminase levels and hepatic scores of stage, grade, and steatosis were higher in patients with REC iron staining than in those without. REC iron scores were independently associated with advanced stage. Serum sTNFR2 levels were significantly higher in patients with REC iron than in those without. REC iron scores were independently correlated with sTNFR2 levels. Compared with patients without stainable iron, those with iron overload had decreased ratios of hepcidin mRNA to serum ferritin. The efficacy of phlebotomy was greater in patients with REC iron than in those without REC iron. Conclusions. The present results show the importance of REC iron for the development of CHepC and the therapeutic effect of phlebotomy in CHepC. Hironori Mitsuyoshi, Kohichiroh Yasui, Kanji Yamaguchi, Masahito Minami, Takeshi Okanoue, and Yoshito Itoh Copyright © 2013 Hironori Mitsuyoshi et al. All rights reserved. Prevention and Management of Variceal Hemorrhage Sun, 31 Mar 2013 18:35:14 +0000 Variceal hemorrhage is a common and devastating complication of portal hypertension and is a leading cause of death in patients with cirrhosis. The management of gastroesophageal varices has evolved over the last decade resulting in improved mortality and morbidity rates. Regarding the primary prevention of variceal hemorrhaging, nonselective β-blockers should be the first-line therapy in all patients with medium to large varices and in patients with small varices associated with high-risk features such as red wale marks and/or advanced cirrhosis. EVL should be offered in cases of intolerance or side effects to β-blockers, or for patients at high-risk for variceal bleeding who have medium or large varices with red wale marks or advanced liver cirrhosis. In acute bleeding, vasoactive agents should be initiated along with antibiotics followed by EVL or endoscopic sclerotherapy (if EVL is technically difficult) within the first 12 hours of presentation. Where available, terlipressin is the preferred agent because of its safety profile and it represents the only drug with a proven efficacy in improving survival. All patients surviving an episode of bleeding should undergo further prophylaxis to prevent rebleeding with EVL and nonselective β-blockers. Dong Hyun Kim and Jun Yong Park Copyright © 2013 Dong Hyun Kim and Jun Yong Park. All rights reserved. Hepatic Manifestations in Hematological Disorders Sun, 31 Mar 2013 16:03:29 +0000 Liver involvement is often observed in several hematological disorders, resulting in abnormal liver function tests, abnormalities in liver imaging studies, or clinical symptoms presenting with hepatic manifestations. In hemolytic anemia, jaundice and hepatosplenomegaly are often seen mimicking liver diseases. In hematologic malignancies, malignant cells often infiltrate the liver and may demonstrate abnormal liver function test results accompanied by hepatosplenomegaly or formation of multiple nodules in the liver and/or spleen. These cases may further evolve into fulminant hepatic failure. Jun Murakami and Yukihiro Shimizu Copyright © 2013 Jun Murakami and Yukihiro Shimizu. All rights reserved. Targeting the HGF-cMET Axis in Hepatocellular Carcinoma Sun, 31 Mar 2013 14:25:11 +0000 Under normal physiological conditions, the hepatocyte growth factor (HGF) and its receptor, the MET transmembrane tyrosine kinase (cMET), are involved in embryogenesis, morphogenesis, and wound healing. The HGF-cMET axis promotes cell survival, proliferation, migration, and invasion via modulation of epithelial-mesenchymal interactions. Hepatocellular cancer (HCC) is the third most common cause of worldwide cancer-related mortality; advanced disease is associated with a paucity of therapeutic options and a five-year survival rate of only 10%. Dysregulation of the HGF-cMET pathway is implicated in HCC carcinogenesis and progression through activation of multiple signaling pathways; therefore, cMET inhibition is a promising therapeutic strategy for HCC treatment. The authors review HGF-cMET structure and function in normal tissue and in HCC, cMET inhibition in HCC, and future strategies for biomarker identification. Neeta K. Venepalli and Laura Goff Copyright © 2013 Neeta K. Venepalli and Laura Goff. All rights reserved.