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Challenges in the treatment of chronic hepatitis C in the HIV/HCV-coinfected patient.

Wed, 05/22/2013 - 10:05
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Challenges in the treatment of chronic hepatitis C in the HIV/HCV-coinfected patient.

Expert Rev Anti Infect Ther. 2012 Oct;10(10):1117-28

Authors: Rodríguez-Torres M

Abstract
Hepatitis C virus (HCV) and HIV are common coinfections that convey a shortened lifespan, mostly related to liver disease. Treatment against HCV in the coinfected patient is notoriously more complex and challenging. There are no optimal treatment algorithms for HIV/HCV coinfected patients as efficacy of approved anti-HCV therapies is low with relevant side effects. The use of direct-acting antivirals for anti-HCV therapy has the potential to improve therapeutic efficacy, but also increase side effects and drug-drug interactions. In spite of all of this, the most important and significant fact is that chronic hepatitis C is potentially curable, and the eradication of the HCV infection is a crucial outcome in this population. The establishment of a productive collaboration among the regulatory agencies, the medical community and the pharmaceutical industry could lead to faster access to more effective HCV therapies for the coinfected patient and eventually stop the progression of liver disease in these patients.

PMID: 23199398 [PubMed - indexed for MEDLINE]

Increased serum levels of quinolinic acid indicate enhanced severity of hepatic dysfunction in patients with liver cirrhosis.

Wed, 05/22/2013 - 10:05
Related Articles

Increased serum levels of quinolinic acid indicate enhanced severity of hepatic dysfunction in patients with liver cirrhosis.

Hum Immunol. 2013 Jan;74(1):60-6

Authors: Lahdou I, Sadeghi M, Oweira H, Fusch G, Daniel V, Mehrabi A, Jung G, Elhadedy H, Schmidt J, Sandra-Petrescu F, Iancu M, Opelz G, Terness P, Schefold JC

Abstract
BACKGROUND: The Model for End-Stage Liver Disease (MELD) score is a tool for assessment of the degree of hepatic insufficiency/failure. Quinolinic acid (QuinA) is a tryptophan metabolite produced by activated macrophages. Here we investigate whether the degree of systemic inflammation (QuinA, neopterin, CRP and IL-6) correlates with clinical liver dysfunction according to the MELD Score.
METHOD: Ninety-four patients with liver cirrhosis were categorized into 2 groups according to baseline MELD score (group I, MELD <20, n = 61, and group II, MELD ≥20, n = 33).
RESULTS: Serum levels of QuinA, neopterin, CRP, and IL-6 significantly correlated with MELD score (r = 0.77, 0.75, 0.57, and 0.50; p < 0.0001, respectively). Patients of group II had significantly higher serum levels of QuinA, neopterin, CRP, and IL-6 than group I (p0.0001). ROC curve analysis showed that QuinA and neopterin are more sensitive markers for severity of liver disease than established markers of inflammation such as CRP and IL-6 (sensitivity = 86% and 79%, respectively) (AUC=0.89 and 0.89, respectively). QuinA provided the most sensitive index with regard to the identification of patients with hepatic encephalopathy.
CONCLUSION: Serum levels of QuinA reflect the degree of liver dysfunction. Moreover, high levels of QuinA may serve as a sensitive indicator of hepatic encephalopathy.

PMID: 23046794 [PubMed - indexed for MEDLINE]

Bevacizumab - finding its niche in the treatment of heart failure secondary to liver vascular malformations in hereditary hemorrhagic telangiectasia.

Tue, 05/21/2013 - 10:09

Bevacizumab - finding its niche in the treatment of heart failure secondary to liver vascular malformations in hereditary hemorrhagic telangiectasia.

Hepatology. 2013 May 17;

Authors: Young LH, Henderson KJ, White RI, Garcia-Tsao G

Abstract
CONTEXT: The only treatment available to restore normal cardiac output in patients with hereditary hemorrhagic telangiectasia (HHT) and cardiac failure is liver transplant. Anti-vascular endothelial growth factor treatments such as bevacizumab may be an effective treatment. OBJECTIVES: To test the efficacy of bevacizumab in reducing high cardiac output in severe hepatic forms of HHT and to assess improvement in epistaxis duration and quality of life. DESIGN, SETTING, AND PATIENTS: Single-center, phase 2 trial with national recruitment from the French HHT Network. Patients were 18 to 70 years old and had confirmed HHT, severe liver involvement, and a high cardiac index related to HHT. INTERVENTION: Bevacizumab, 5 mg per kg, every 14 days for a total of 6 injections. The total duration of the treatment was 2.5 months; patients were followed up for 6 months after the beginning of the treatment. MAIN OUTCOME MEASURE: Decrease in cardiac output at 3 months after the first injection, evaluated by echocardiography. RESULTS: A total of 25 patients were included between March 2009 and November 2010. Of the 24 patients who had echocardiograms available for reread, there was a response in 20 of 24 patients with normalization of cardiac index (complete response [CR]) in 3 of 24, partial response (PR) in 17 of 24, and no response in 4 cases. Median cardiac index at beginning of the treatment was 5.05 L/min/m2 (range, 4.1-6.2) and significantly decreased at 3 months after the beginning of the treatment with a median cardiac index of 4.2 L/min/m2 (range, 2.9-5.2; P<001). Median cardiac index at 6 months was significantly lower than before treatment (4.1 L/min/m2; range, 3.0- 5.1). Among 23 patients with available data at 6 months, we observed CR in 5 cases, PR in 15 cases, and no response in 3 cases. Mean duration of epistaxis, which was 221 minutes per month (range, 0-947) at inclusion, had significantly decreased at 3 months (134 minutes; range, 0-656) and 6 months (43 minutes; range, 0-310) (P=.008). Quality of life had significantly improved. The most severe adverse events were 2 cases of grade 3 systemic hypertension, which were successfully treated. CONCLUSION: In this preliminary study of patients with HHT associated with severe hepatic vascular malformations and high cardiac output, administration of bevacizumab was associated with a decrease in cardiac output and reduced duration and number of episodes of epistaxis. (HEPATOLOGY 2013.).

PMID: 23686865 [PubMed - as supplied by publisher]

Preoperative 4-Week Supplementation with Omega-3 Polyunsaturated Fatty Acids Reduces Liver Volume and Facilitates Bariatric Surgery in Morbidly Obese Patients.

Tue, 05/21/2013 - 10:09

Preoperative 4-Week Supplementation with Omega-3 Polyunsaturated Fatty Acids Reduces Liver Volume and Facilitates Bariatric Surgery in Morbidly Obese Patients.

Obes Surg. 2013 May 19;

Authors: Iannelli A, Martini F, Schneck AS, Ghavami B, Baudin G, Anty R, Gugenheim J

Abstract
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a very common condition among obese patients that may lead to the enlargement of the liver, that in turn impairs the access to the gastro-esophageal junction during laparoscopic bariatric surgery. Omega-3 polyunsaturated fatty acids (Ω-3 PUFAs) supplementation has been shown to reduce nutritional hepatic steatosis. The aim of this study was to assess the effects of a 4-week course of oral Ω-3 PUFAs supplementation on the volume of the liver. METHODS: 20 morbidly obese patients were administered oral Ω-3 PUFAs (1,500 mg daily) for 4 weeks before undergoing the laparoscopic Roux-en-Y gastric bypass (LRYGBP) without any dietary restriction. The volume of the left hepatic lobe was estimated by liver ultrasonography at baseline and at the end of treatment. The degree of difficulty to access the gastro-esophageal junction was appreciated subjectively by the operating surgeon. RESULTS: All patients completed the study and no side effect was reported. The mean volume of the left hepatic lobe decreased by 20 % from 598 ± 97 to 484 ± 118 cm(3) after the treatment (p = 0.002). The access to the gastro-esophageal junction was reported as simple, with easy retraction of the left hepatic lobe by the operating surgeon in all cases. CONCLUSIONS: This study demonstrates that a 4-week course of oral Ω-3 PUFAs supplementation results in a significant reduction in liver size that facilitates the LRYGBP.

PMID: 23686653 [PubMed - as supplied by publisher]

Open preperitoneal mesh repair of inguinal hernias using a mesh with nitinol memory frame.

Tue, 05/21/2013 - 10:09

Open preperitoneal mesh repair of inguinal hernias using a mesh with nitinol memory frame.

Hernia. 2013 May 21;

Authors: Berrevoet F, Vanlander A, Bontinck J, Troisi RI

Abstract
PURPOSE: To prospectively evaluate the use of a continuous Nitinol containing memory frame patch during a TIPP-technique in the open repair of inguinal and femoral hernias. METHODS: Over a 3-year period all consecutive adult patients that needed treatment for an inguinal or femoral hernia were treated by the TIPP repair using the Rebound Shield mesh. Intra-operatively the type and size of the hernia were evaluated according to the EHS classification, as well as the size of the mesh used. Baseline characteristics for all patients were evaluated considering age, gender, BMI and American society of Anesthesiologists score. Standard X-ray was performed to evaluate mesh position. All patients were evaluated for post-operative pain using the visual analogue scale (VAS 0-10 scale). RESULTS: In total 289 groin hernias were operated using a nitinol containing patch in 235 patients. The mean operating time was 38 min for unilateral hernias and 59 min for bilateral hernias. The median follow-up is 21.2 months (14-33 months) during which three patients died, unrelated to the groin hernia repair. At the time of re-evaluation 12 patients (5.0 %) complained of chronic pain, with a VAS score higher than 3 after 3 months (range 3-10). Two of these patients already had severe pain pre-operatively. A total of 3 recurrences (2.9 %) were noted with strong correlation with X-ray findings. CONCLUSION: A nitinol memory frame containing mesh is a valuable tool to achieve complete deployment of a large pore mesh in a TIPP repair for inguinal hernias with acceptable morbidity and a low recurrence rate.

PMID: 23686406 [PubMed - as supplied by publisher]

A bystander cell-based GM-CSF secreting vaccine synergizes with a low dose of cyclophosphamide and induces therapeutic immune responses against murine hepatocellular carcinoma.

Tue, 05/21/2013 - 10:09

A bystander cell-based GM-CSF secreting vaccine synergizes with a low dose of cyclophosphamide and induces therapeutic immune responses against murine hepatocellular carcinoma.

Cell Mol Immunol. 2013 May 20;

Authors: Chen C, Hou J, Lin Z, Yao M, Jiang R, Wang Y, Gao Y, Shao Q, Deng L, Chen Y, Sun B

Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting cellular tumor vaccines contribute to the induction of potent antitumor immune responses in murine models and patients suffering from cancers. Hepatocellular carcinoma (HCC) is one of the most frequent and malignant cancers in China. We describe, for the first time, a GM-CSF releasing vaccine strategy that represents a step toward combating this type of cancer. In this study, a bystander cell-based GM-CSF secreting vaccine against murine HCC, Hepa1-6/B78H1-GM-CSF, was co-administered with a low dose of cyclophosphamide (CY). After challenging with tumor and vaccination, immunological assays demonstrated that the cellular antitumor immune responses were efficiently activated and that tumor development was significantly retarded, which was dependent on synergy with CY. The promising outcome of the anti-HCC vaccine in the murine model demonstrates the feasibility of a future clinical application for this treatment in HCC patients.Cellular & Molecular Immunology advance online publication, 20 May 2013; doi:10.1038/cmi.2013.20.

PMID: 23686226 [PubMed - as supplied by publisher]

Manufacturing Devices and Instruments for Easier Rat Liver Transplantation.

Tue, 05/21/2013 - 10:09

Manufacturing Devices and Instruments for Easier Rat Liver Transplantation.

J Vis Exp. 2013;(75)

Authors: Oldani G, Lacotte S, Orci L, Morel P, Mentha G, Toso C

Abstract
Orthotopic rat liver transplantation is a popular model, which has been shown in a recent JoVE paper with the use of the "quick-linker" device. This technique allows for easier venous cuff-anatomoses after a reasonable learning curve. The device is composed of two handles, which are carved out from scalpel blades, one approximator, which is obtained by modifying Kocher's forceps, and cuffs designed from fine-bore polyethylene tubing. The whole process can be performed at a low-cost using common laboratory material. The present report provides a step-by-step protocol for the design of the required pieces and includes stencils.

PMID: 23685736 [PubMed - as supplied by publisher]

Regulatory T Cells Inhibit Th1 Cell-Mediated Bile Duct Injury in Murine Biliary Atresia.

Tue, 05/21/2013 - 10:09

Regulatory T Cells Inhibit Th1 Cell-Mediated Bile Duct Injury in Murine Biliary Atresia.

J Hepatol. 2013 May 14;

Authors: Tucker RM, Feldman AG, Fenner EK, Mack CL

Abstract
BACKGROUND AND AIMS: Biliary atresia (BA) is a pediatric inflammatory disease of the biliary system which leads to cirrhosis and the need for liver transplantation. One theory regarding etiology is that bile duct injury is due to virus-induced autoreactive T cell-mediated inflammation. Regulatory T cells (Treg) abnormalities in BA could result in unchecked bystander inflammation and autoimmunity targeting bile ducts. The aim of this study was to determine if Tregs are dysfunctional in the rotavirus-induced mouse model of BA (murine BA). METHODS AND RESULTS: Murine BA resulted from infection of BALB/c neonates with Rhesus rotavirus (RRV). Liver Tregs from BA mice were decreased in number, activation marker expression and suppressive function. Adoptive transfer studies revealed that RRV-infected mice that received Tregs had significantly increased survival (84%) compared to controls (12.5%). In addition, ablation of Tregs in older mice, followed by RRV infection, resulted in increased bile duct injury. CONCLUSION: These studies demonstrate that dysregulation of Tregs is present in murine BA and that diminished Treg function may be implicated in the pathogenesis of human BA.

PMID: 23685050 [PubMed - as supplied by publisher]

Augmented environments for the targeting of hepatic lesions during image-guided robotic liver surgery.

Tue, 05/21/2013 - 10:09

Augmented environments for the targeting of hepatic lesions during image-guided robotic liver surgery.

J Surg Res. 2013 May 8;

Authors: Buchs NC, Volonte F, Pugin F, Toso C, Fusaglia M, Gavaghan K, Majno PE, Peterhans M, Weber S, Morel P

Abstract
BACKGROUND: Stereotactic navigation technology can enhance guidance during surgery and enable the precise reproduction of planned surgical strategies. Currently, specific systems (such as the CAS-One system) are available for instrument guidance in open liver surgery. This study aims to evaluate the implementation of such a system for the targeting of hepatic tumors during robotic liver surgery. MATERIAL AND METHODS: Optical tracking references were attached to one of the robotic instruments and to the robotic endoscopic camera. After instrument and video calibration and patient-to-image registration, a virtual model of the tracked instrument and the available three-dimensional images of the liver were displayed directly within the robotic console, superimposed onto the endoscopic video image. An additional superimposed targeting viewer allowed for the visualization of the target tumor, relative to the tip of the instrument, for an assessment of the distance between the tumor and the tool for the realization of safe resection margins. RESULTS: Two cirrhotic patients underwent robotic navigated atypical hepatic resections for hepatocellular carcinoma. The augmented endoscopic view allowed for the definition of an accurate resection margin around the tumor. The overlay of reconstructed three-dimensional models was also used during parenchymal transection for the identification of vascular and biliary structures. Operative times were 240 min in the first case and 300 min in the second. There were no intraoperative complications. CONCLUSIONS: The da Vinci Surgical System provided an excellent platform for image-guided liver surgery with a stable optic and instrumentation. Robotic image guidance might improve the surgeon's orientation during the operation and increase accuracy in tumor resection. Further developments of this technological combination are needed to deal with organ deformation during surgery.

PMID: 23684617 [PubMed - as supplied by publisher]

Assessment and management of cerebral edema and intracranial hypertension in acute liver failure.

Tue, 05/21/2013 - 10:09

Assessment and management of cerebral edema and intracranial hypertension in acute liver failure.

J Crit Care. 2013 May 14;

Authors: Mohsenin V

Abstract
Acute liver failure is uncommon but not a rare complication of liver injury. It can happen after ingestion of acetaminophen and exposure to toxins and hepatitis viruses. The defining clinical symptoms are coagulopathy and encephalopathy occurring within days or weeks of the primary insult in patients without preexisting liver injury. Acute liver failure is often complicated by multiorgan failure and sepsis. The most life-threatening complications are sepsis, multiorgan failure, and brain edema. The clinical signs of increased intracranial pressure (ICP) are nonspecific except for neurologic deficits in impending brain stem herniation. Computed tomography of the brain is not sensitive enough in gauging intracranial hypertension or ruling out brain edema. Intracranial pressure monitoring, transcranial Doppler, and jugular venous oximetry provide valuable information for monitoring ICP and guiding therapeutic measures in patients with encephalopathy grade III or IV. Osmotic therapy using hypertonic saline and mannitol, therapeutic hypothermia, and propofol sedation are shown to improve ICPs and stabilize the patient for liver transplantation. In this article, diagnosis and management of hepatic encephalopathy and cerebral edema in patients with acute liver failure are reviewed.

PMID: 23683564 [PubMed - as supplied by publisher]

Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma - Results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience.

Tue, 05/21/2013 - 10:09

Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma - Results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience.

Eur J Cancer. 2013 May 15;

Authors: Weeda VB, Murawski M, McCabe AJ, Maibach R, Brugières L, Roebuck D, Fabre M, Zimmermann A, Otte JB, Sullivan M, Perilongo G, Childs M, Brock P, Zsíros J, Plaschkes J, Czauderna P, Aronson DC

Abstract
PURPOSE: Fibrolamellar hepatocellular carcinoma (FL-HCC) and conventional hepatocellular carcinoma (HCC) cases in two consecutive paediatric HCC trials were analysed to compare outcome and derive treatment implications. PATIENTS AND METHODS: Data of 24 FL-HCC (24% PRETEXT IV) and 38 HCC (42% PRETEXT IV) cases from SIOPEL-2 and -3 (1995-1998, 1998-2006) were analysed. Patients were treated according to SIOPEL-2 and -3 high-risk protocol (carboplatin+doxorubicin alternating with cisplatin; seven preoperative, three postoperative cycles) or with primary surgery followed by chemotherapy as indicated. RESULTS: Thirteen of 24 FL-HCC (54%) and 32/38 HCC (84%) were initially treated with chemotherapy. Eight FL-HCC (33%) and five HCC patients (13%) had primary surgery. Partial response was observed in 31% of FL-HCC versus 53% of HCC patients (p=0.17). Complete resection was achieved in ten FL-HCC and seven HCC patients (p=0.08). Three-year event free survival (EFS) was 22% for FL-HCC versus 28% for HCC. Overall survival (OS) was not significantly different at 3 years follow up (42% for FL-HCC versus 33% for HCC, p=0.24). EFS/OS Kaplan-Meier curves did not differ significantly, with median follow up of 43 (FL-HCC) and 60 (HCC) months. No significant correlation was found between potential prognostic factors and OS. In the entire cohort nine out of 23 (39%) patients with complete resection or orthotopic liver transplantation versus 34/39 (87%) without successful surgical treatment, died. CONCLUSIONS: Long-term OS in FL-HCC and HCC is similar. With low response rates, complete resection remains the treatment of choice.

PMID: 23683550 [PubMed - as supplied by publisher]

[Severe toxic acute liver failure: Etiology and treatment.]

Tue, 05/21/2013 - 10:09

[Severe toxic acute liver failure: Etiology and treatment.]

Ann Fr Anesth Reanim. 2013 May 14;

Authors: Amathieu R, Levesque E, Merle JC, Chemit M, Costentin C, Compagnon P, Dhonneur G

Abstract
Many substances, drugs or not, can be responsible for acute hepatitis. Nevertheless, toxic etiology, except when that is obvious like in acetaminophen overdose, is a diagnosis of elimination. Major causes, in particular viral etiologies, must be ruled out. Acetaminophen, antibiotics, antiepileptics and antituberculous drugs are the first causes of drug-induced liver injury. Severity assessment of the acute hepatitis is critical. Acute liver failure (ALF) is defined by the factor V, respectively more than 50% for the mild ALF and less than 50% for the severe ALF. Neurological examination must be extensive to the search for encephalopathy signs. According to the French classification, fulminant hepatitis is defined by the presence of an encephalopathy in the two first weeks and subfulminant between the second and 12th week after the advent of the jaundice. During acetaminophen overdose, with or without hepatitis or ALF, intravenous N-acetylcysteine must be administered as soon as possible. In the non-acetaminophen related ALF, N-acetylcysteine improves transplantation-free survival. Referral and assessment in a liver transplantation unit should be discussed as soon as possible.

PMID: 23683460 [PubMed - as supplied by publisher]

Repopulation of the immunosuppressed retrorsine-treated infant rat liver with human hepatocytes.

Tue, 05/21/2013 - 10:09

Repopulation of the immunosuppressed retrorsine-treated infant rat liver with human hepatocytes.

Xenotransplantation. 2013 May 20;

Authors: Tachibana A, Tateno C, Yoshizato K

Abstract
BACKGROUND: We previously generated humanized chimeric mice by transplanting h-hepatocytes into the livers of the diseased-liver transgenic mouse model with immunodeficient background. These mice with livers mostly replaced by human (h) hepatocytes have been proved to be useful for research on drug metabolism and toxicity and on intrahepatic pathogens such as hepatitis. However, their small body size prohibited collecting sufficient biological samples and made surgical manipulation difficult, which motivated us to produce humanized larger animal(s) bearing h-hepatocytes. METHODS: Fischer 344 (F344) rats at 2 weeks of age were administrated with hepatotoxin retrorsine (RS) and then transplanted with syngeneic F344 rat (r)- or h-hepatocytes via the portal vein. The hosts were injected daily with FK506 immunosuppressant. The livers were harvested periodically for determining donor-cell replacement ratios and compared with those of the humanized chimeric mice, and liver-specific mRNA and protein expressions by immunohistochemistry and reverse-transcription PCR. RESULTS: RS treatment of infant rats inhibited hepatocyte proliferation, resulting in decreased liver weight and megalocytic changes in hepatocytes. R-hepatocytes transplanted into RS-treated rats engrafted into and repopulated the liver at ratios of 16.4 ± 6.7% and 48.3 ± 29.3% at 3 and 6 weeks after transplantation, respectively. H-hepatocytes also engrafted into the rat liver and showed a repopulation ratio of 2.5 ± 1.5% at 3 weeks post-transplantation, which was comparable to the ratio in the humanized chimeric mouse model at least until 3 weeks. Propagated h-hepatocytes in the rat liver expressed hepatocyte-specific mRNA and proteins at least 3 weeks after transplantation. CONCLUSIONS: Xenogeneic hepatocytes were able to engraft rat liver and grow well therein for at least 3 weeks post-transplantation in rats when immunosuppression was combined appropriately with liver injury at comparable levels to the well-characterized humanized chimeric mouse model.

PMID: 23683097 [PubMed - as supplied by publisher]

The best way to prevent cytomegalovirus infection after liver transplantation: the debate goes on.

Tue, 05/21/2013 - 10:09

The best way to prevent cytomegalovirus infection after liver transplantation: the debate goes on.

Transpl Int. 2013 Jun;26(6):590-591

Authors: Metselaar HJ, van Campenhout MJ, van der Eijk AA

PMID: 23682670 [PubMed - as supplied by publisher]

Highly Efficient Differentiation of Functional Hepatocytes From Human Induced Pluripotent Stem Cells.

Sat, 05/18/2013 - 10:13

Highly Efficient Differentiation of Functional Hepatocytes From Human Induced Pluripotent Stem Cells.

Stem Cells Transl Med. 2013 May 16;

Authors: Ma X, Duan Y, Tschudy-Seney B, Roll G, Behbahan IS, Ahuja TP, Tolstikov V, Wang C, McGee J, Khoobyari S, Nolta JA, Willenbring H, Zern MA

Abstract
Human induced pluripotent stem cells (hiPSCs) hold great potential for use in regenerative medicine, novel drug development, and disease progression/developmental studies. Here, we report highly efficient differentiation of hiPSCs toward a relatively homogeneous population of functional hepatocytes. hiPSC-derived hepatocytes (hiHs) not only showed a high expression of hepatocyte-specific proteins and liver-specific functions, but they also developed a functional biotransformation system including phase I and II metabolizing enzymes and phase III transporters. Nuclear receptors, which are critical for regulating the expression of metabolizing enzymes, were also expressed in hiHs. hiHs also responded to different compounds/inducers of cytochrome P450 as mature hepatocytes do. To follow up on this observation, we analyzed the drug metabolizing capacity of hiHs in real time using a novel ultraperformance liquid chromatography-tandem mass spectrometry. We found that, like freshly isolated primary human hepatocytes, the seven major metabolic pathways of the drug bufuralol were found in hiHs. In addition, transplanted hiHs engrafted, integrated, and proliferated in livers of an immune-deficient mouse model, and secreted human albumin, indicating that hiHs also function in vivo. In conclusion, we have generated a method for the efficient generation of hepatocytes from induced pluripotent stem cells in vitro and in vivo, and it appears that the cells function similarly to primary human hepatocytes, including developing a complete metabolic function. These results represent a significant step toward using patient/disease-specific hepatocytes for cell-based therapeutics as well as for pharmacology and toxicology studies.

PMID: 23681950 [PubMed - as supplied by publisher]

Inflammation and liver tumorigenesis.

Sat, 05/18/2013 - 10:13

Inflammation and liver tumorigenesis.

Front Med. 2013 May 17;

Authors: Sun B, Karin M

Abstract
Inflammation has been considered as one of the hallmarks of cancer, and chronic hepatitis is a major cause of liver cancer. This review will focus on the pathogenic role of inflammation in hepatocarcinogenesis and will discuss recent advances in understanding the chronic hepatitis-liver cancer link based on hot spots in liver cancer research, including cellular interaction, cytokines, microRNA and stem cells. All of these mechanisms should be taken into consideration because they are crucial for the development of more efficacious therapeutic strategies for preventing and treating human chronic hepatitis and hepatocellular carcinoma.

PMID: 23681888 [PubMed - as supplied by publisher]

Primary gastrointestinal stromal tumor of the liver: report of a case.

Sat, 05/18/2013 - 10:13

Primary gastrointestinal stromal tumor of the liver: report of a case.

Surg Today. 2013 May 17;

Authors: Zhou B, Zhang M, Yan S, Zheng S

Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They can occur anywhere in the gastrointestinal tract, and rarely outside the digestive tract. We herein report a case of primary gastrointestinal stromal tumor that was resected from the liver of a 56-year-old male, which is the sixth description of a primary hepatic gastrointestinal stromal tumor. The tumor was shown to be completely limited within the liver by radiological, intraoperative and pathological examinations. The pathological results demonstrated an intermediate risk gastrointestinal stromal tumor, and immunohistochemical expression of CD117 was positive. Although rare, we suggested that GISTs should be considered in the differential diagnosis of hepatic nodules, and that not all hepatic gastrointestinal stromal tumors should automatically be considered to be metastases from a primary gastrointestinal site.

PMID: 23681598 [PubMed - as supplied by publisher]

Mucosal pH, Dental Findings, and Salivary Composition in Pediatric Liver Transplant Recipients.

Sat, 05/18/2013 - 10:13

Mucosal pH, Dental Findings, and Salivary Composition in Pediatric Liver Transplant Recipients.

Transplantation. 2013 May 15;

Authors: Davidovich E, Asher R, Shapira J, Brand HS, Veerman EC, Shapiro R

Abstract
BACKGROUND: Oral health and dental maintenance have become part of the standard of care for pediatric liver transplant recipients. These individuals tend to suffer particularly from dental problems, such as gingival enlargement, gingivitis, poor oral hygiene, dental hypoplasia, and caries. Saliva composition influences oral hygiene and disease states. We investigated saliva composition and its association with the oral health of young recipients of liver transplants. METHODS: In 70 patients, 36 liver transplant recipients (ages 2-23 years) and 34 healthy controls (ages 4-21 years), we measured the following variables: (a) oral hygiene, (b) gingival inflammation, (c) caries status, (d) dental calculus formation, (e) oral mucosal pH, and (f) salivary protein composition. RESULTS: Lower mean decayed, missing, and filled teeth index (P=0.0038), higher mean gingival index (P=0.0001), and higher mean calculus score (P=0.003) were found in the transplanted study group compared with the control. The mean mucosal pH for seven intraoral sites was higher in the transplant group (P=0.0006). The median salivary albumin concentration was significantly lower in the transplant group (P=0.01), as was the median salivary albumin/total protein ratio (P=0.0002). CONCLUSIONS: In post-liver transplant pediatric recipients, low incidence of caries, together with high incidence of dental calculus, could be attributed to elevated oral mucosal pH. Salivary albumin and immunoglobulin A levels were relatively low in these patients. Clinicians should pay particular attention to the oral health and dental care of liver transplanted children.

PMID: 23680932 [PubMed - as supplied by publisher]

Hepatopulmonary syndrome and portopulmonary hypertension.

Sat, 05/18/2013 - 10:13

Hepatopulmonary syndrome and portopulmonary hypertension.

Hosp Pract (1995). 2013 Apr;41(2):62-71

Authors: Restrepo R, Singer EF, Baram M, Restrepo R, Singer EF, Baram M

Abstract
Hepatopulmonary syndrome and portopulmonary hypertension are 2 of many diseases that affect the lungs in patients with liver disease. The 2 vascular conditions are often confused. We review both hepatopulmonary syndrome and portopulmonary hypertension to better understand their pathophysiologies, clinical presentations, tools to aid in differentiating and diagnosing the disease states, treatment options, and influences on patient prognosis. We also consider patient viability for liver transplantation.

PMID: 23680738 [PubMed - in process]

Failure of Fibrotic Liver Regeneration in Mice is Linked to a Severe Fibrogenic Response Driven by Hepatic Progenitor Cell Activation.

Sat, 05/18/2013 - 10:13

Failure of Fibrotic Liver Regeneration in Mice is Linked to a Severe Fibrogenic Response Driven by Hepatic Progenitor Cell Activation.

Am J Pathol. 2013 May 13;

Authors: Kuramitsu K, Sverdlov DY, Liu SB, Csizmadia E, Burkly L, Schuppan D, Hanto DW, Otterbein LE, Popov Y

Abstract
Failure of fibrotic liver to regenerate after resection limits therapeutic options and increases demand for liver transplantation, representing a significant clinical problem. The mechanism underlying regenerative failure in fibrosis is poorly understood. Seventy percent partial hepatectomy (PHx) was performed in C57Bl/6 mice with or without carbon tetrachloride (CCl4)-induced liver fibrosis. Liver function and regeneration was monitored at 1 to 14 days thereafter by assessing liver mass, alanine aminotransferase (ALT), mRNA expression, and histology. Progenitor (oval) cell mitogen tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and TWEAK-neutralizing antibody were used to manipulate progenitor cell proliferation in vivo. In fibrotic liver, hepatocytes failed to replicate efficiently after PHx. Fibrotic livers showed late (day 5) peak of serum ALT (3542 ± 355I U/L compared to 93 ± 65 IU/L in nonfibrotic), which coincided with progenitor cell expansion, increase in profibrogenic gene expression and de novo collagen deposition. In fibrotic mice, inhibition of progenitor activation using TWEAK-neutralizing antibody after PHx resulted in strongly down-regulated profibrogenic mRNA, reduced serum ALT levels and improved regeneration. Failure of hepatocyte-mediated regeneration in fibrotic liver triggers activation of the progenitor (oval) cell compartment and a severe fibrogenic response. Inhibition of progenitor cell proliferation using anti-TWEAK antibody prevents fibrogenic response and augments fibrotic liver regeneration. Targeting the fibrogenic progenitor response represents a promising strategy to improve hepatectomy outcomes in patients with liver fibrosis.

PMID: 23680654 [PubMed - as supplied by publisher]

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