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Current Issue

January March, 2008

Vol. 7 Issue 1

On the cover: Official Journal of the Mexican Association of Hepatology and the Latin-American Association for the Study of the Liver

FROM THE EDITOR

HEPATOLOGY HIGHLIGHTS

CONCISE REVIEW

  • Treatment of alcoholic liver disease Ashutosh Barve, Rehan Khan, Luis Marsano, Kadiyala V Ravindra, Craig McClain Page 5-15

    Alcoholic Liver Disease (ALD) is a major cause of morbidity and mortality both in the United States and worldwide. In the United States, it is projected that over 2,000,000 persons have ALD, and the mortality for cirrhosis with superimposed alcoholic hepatitis is much worse than that of many common types of cancer. Unfortunately, there is no FDA approved therapy for ALD. We have made major strides in the last decade in identifying mechanisms for the development of liver injury in ALD, and therapies are evolving directed at specific mechanisms. It is clear that life style modification with abstinence, cessation of smoking and weight loss (if overweight) are beneficial. It is also clear that most patients with advanced liver disease have some form of malnutrition, and nutritional supplementation is of benefit. Patients with alcoholic hepatitis that is relatively severe in nature, but not complicated by issues such as infection or GI bleeding, appear to benefit from steroids. A drop in bilirubin should be monitored in steroid treated patients. Pentoxifylline appears to be beneficial in patients with alcoholic hepatitis, especially those with early hepatorenal syndrome. A variety of other agents such as PTU, lecithin, colchicine, and anabolic steroids are probably not effective. Complementary and alternative medicine agents such as zinc, milk thistle, and SAM have great therapeutic rationale. Results of ongoing NIH studies evaluating agents such as specific anti-TNF's, SAM and Milk Thistle are eagerly awaited. Transplantation is clearly an option for end stage ALD in patients who are abstinent.

  • Oxidative stress: A radical way to stop making bile Marcelo G. Roma, Enrique J. Sánchez Pozzi Page 16-33

    Oxidative stress is a common feature in most hepatopathies. In recent years, evidence has accumulated that reactive oxygen species (ROS) induce a number of functional changes either deleterious or adaptive in the capability of the hepatocytes to produce bile and to secrete exogenous and endogenous compounds. This review is aimed to describe the mechanisms involved in these alterations. For this purpose, we will summarize: 1) The current evidence that acutely-induced oxidative stress is cholestatic, by describing the mechanisms underlying the hepatocyte secretory failure, including the disorganization of the actin cytoskeleton and its most noticeable consequences, the impairment of tight-junctional structures and the endocytic internalization of canalicular transporters relevant to bile formation. 2) The role for oxidative-stress-activated signalling pathways in the pathomechanisms described above, particularly those involving Ca2+ elevation and its consequent activation of Ca2+-dependent PKC isoforms. 3) The mechanisms involved in the adaptive response against oxidative stress mediated by ROS-responsive transcription factors, involving up-regulation of GSH-synthesizing enzymes, GSH-detoxifying enzymes and the hepatocellular efflux pumps; this response enhances the co-coordinated inactivation by GSH conjugation of lipid peroxides and their further cellular extrusion. 4) The manner this adaptive response can be surpassed by the sustained production of ROS, thus inducing transcriptional and posttranscriptional changes in transporters relevant to bile formation, as has been shown to occur, for example, after long-term administration of aluminum to rats, in the Long-Evans Cinnamon rat (a model of chronic hepatic copper accumulation mimicking Wilson's disease), and in ischemia-reperfusion injury.

  • Oncolytic virotherapy Daniel Cervantes-García, Rocío Ortiz-López, Netzahualcoyotl Mayek-Pérez, Augusto Rojas-Martínez Page 34-45

    Current oncolytic virotherapy strategies are based in the accumulated understanding of the common molecular mechanisms displayed during cell transformation and viral infection, like cell cycle and apoptosis deregulations. Oncolytic virotherapy aims to achieve a strong cytolytic effect, highly restricted to transformed cells. Here, we describe the oncolytic virotherapy defined as the use of viruses like antitumor agents (wild and gene-modified oncolytic viruses) and the developed strategies to increase antitumor efficacy and safety. In addition, we discuss the advances and challenges concerning the use virotherapy in animal models and clinical trials. Some clinical trials of virotherapy have demonstrated promising results, particularly when combined with standard antineoplastic therapies. These preliminary accomplishments are opening the field for more research in several aspects, like vector modifications, pharmacodynamics, biosafety, new clinical applications, etc.

  • Sorafenib, a systemic therapy for hepatocellular carcinoma Nahum Méndez-Sánchez, Francisco Vásquez-Fernández, Daniel Zamora-Valdés, Uribe Misael Page 46-51

    Hepatocellular carcinoma is a lethal disease that requires a multidisciplinary approach and management. Surgical therapy offers long-term survival; however, few patients are candidates. There has been no accepted systemic therapy for this disease until recently. This article briefly discusses the role of RAS/RAF/MEK/ ERK signaling pathway in the pathogenesis of the disease and the promising role of sorafenib for advanced disease.

ORIGINAL ARTICLES

  • Clinicopathologic features of dual chronic hepatitis B and C infection: A comparison with single hepatitis B, C and delta infections Hakan Senturk, Veysel Tahan, Billur Canbakan, Faysal Dane, Yakup Ulger, Resat Ozaras, Fehmi Tabak, Ali Mert, Gulsen Ozbay Page 52-58

    There is controversial data in the literature about the characteristics or features of dual hepatitis B and C infection. Several studies have reported that the dual infection has a more severe histological picture; faster progression leading to cirrhosis and a higher risk for hepatocellular carcinoma compared with the single infections. These findings have not yet been supported. We assessed the patients with dual hepatitis B and C infection with respect to their different features in our country. Method: the chronic hepatitis patients of our clinics were tested, and both HBsAg and anti-HCV positive patients with chronic hepatitis were enrolled to the study. All patients were tested for the biochemical parameters and the presence of HBV-DNA and HCVRNA. Results: Of the 1950 patients, 51 (2.6%) were both HBsAg and anti-HCV positive and 67 were antidelta positive. Patients were followed up for 5.4 ± 2.1 years. Of the 51 dual hepatitis patients, 6 had no HBVDNA and HCV-RNA detectable by PCR, 36 were only HCV-RNA positive, 9 were only HBV-DNA positive and 3 were both HBV-DNA and HCV-RNA positive. Dominant infection in ¾ of the patients was hepatitis C. Clinical and histological properties of the cases with dual Hepatitis B and C infection showed no significant differences compared to the single infections. In conclusion, regarding the prognosis, no significant differences were found between such dual and single infections. Dual infection with hepatitis B virus and delta virus is a significantly more severe condition than the dual infection with hepatitis B and C viruses.

  • Prevalence of dengue infection in north Indian children with acute hepatic failure Rashmi Kumar, Piyush Tripathi, Sanjeev Tripathi, Alok Kanodia, Vimala Venkatesh Page 59-62

    Hepatic manifestations of dengue viral infection are well known and cases of acute hepatic failure (AHF) with evidence of dengue infection are reported. Objectives: To study the role of dengue infection in AHF presenting to hospital. Methods: Setting: Pediatric wards of a teaching hospital in northern India. Subjects: Consecutive children hospitalized with AHF over a 3 month period in 2006. Clinical and laboratory details of subjects were charted. ELISA tests for dengue IgM were done in all patients using commercial kits. Real time PCR assays for dengue genome were done in randomly chosen subjects from those testing positive and negative for IgM. A PCR positive case was considered as definite dengue infection, while those who were only IgM positive were considered as 'probable' dengue. Results: Between July and September 2006, 27 patients were enrolled. Thirteen were unequivocally positive for dengue IgM. A random sample of 7 IgM positive and 3 IgM negative patients was tested by PCR, of which 4 IgM positive and one IgM negative patients were PCR positive. Prevalence of definite dengue infection in AHF was therefore 5/27 or 18.5%. No significant differences were observed in clinical and laboratory features of dengue and nondengue aHF. Conclusions: Dengue infection should be considered in the etiology of AHF in this part of the world. Clinico-laboratory differentiating features of dengue AHF should be studied in a larger sample of patients.

  • Liver biochemistry abnormalities in a quaternary care lipid clinic database Holly A.R. Wiesinger, J. Shah, A. White, E.M. Yoshida, J. Frohlich, S. Sirrs, S. Gill, M.F. Byrne Page 63-66

    Background: The metabolic syndrome and non-alcoholic fatty liver disease are increasing at alarming rates. Aims: To determine the effect of HMG-CoA reductase inhibitors (statins) on elevated liver enzymes in patients with hyperlipidemia. Patients: Patients with AST above 60 U/L prior to or during treatment with statin therapy at a quaternary care lipid clinic were reviewed. Methods: A retrospective analysis was conducted. Patients were separated into two groups: Group 1 – elevated AST prior to statin therapy; and Group 2 – elevated AST during statin therapy. Results: Forty six patients with one or more measurements of AST >60 U/L remained after exclusion criteria were applied. Ten of 13 (77%) group 1 patients had reduced AST levels after initiation of statin therapy. Thirty two of 33 patients (97%) in group 2 had transient AST elevations while on statin therapy; one patient had persistently elevated AST after initiation of treatment. There were no significant adverse events reported. Conclusion: Use of HMG-CoA reductase inhibitors in patients with elevated AST resulted in normalization of AST levels. HMG-CoA reductase inhibitors were safe in patients with mildly elevated AST. This may translate to use of HMG-CoA reductase inhibitors in diseases such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

  • Hepatic expression of ghrelin and adiponectin and their receptors in patients with nonalcoholic fatty liver disease Misael Uribe, Daniel Zamora-Valdés, Mucio Moreno-Portillo, Luisa Bermejo-Martínez, Raúl Pichardo-Bahena, Hector A. Baptista-González, Guadalupe Ponciano-Rodríguez, Martha H. Uribe, Roberto Medina-Santillán, Nahum Méndez-Sánchez Page 67-71

    Background&aim: Adiponectin and ghrelin are hormones that participate in hepatic lipid metabolism, and their expression in liver tissue could have important implications for nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the hepatic expression of ghrelin, adiponectin, AdipoR, and IL-6 in patients with NAFLD and normal liver. Methods: We studied patients with clinical-pathological diagnosis of NAFLD or a normal liver. Patients were classified according to their diagnosis into three groups: normal liver, nonalcoholic hepatic steatosis, and nonalcoholic steatohepatitis (NASH). Adiponectin, AdipoR1, AdipoR2, IL-6, and ghrelin mRNA levels were assessed in biopsies by reverse transcriptasepolymerase chain reaction. Results: Of the 21 patients, three had a normal liver biopsy, 14 had nonalcoholic steatosis, and four had NASH. Patients with NAFLD exhibited significantly higher HOMA-IR and triglyceride concentration (both P < 0.05). There was a nonsignificant trend towards higher ghrelin expression in patients with NASH > nonalcoholic steatosis > normal liver. Patients with NASH had significantly higher mRNA adiponectin levels and lower IL-6 levels than did those with a normal liver (P < 0.05). AdipoR expression did not differ significantly between groups. Conclusion: Adiponectin overexpression was observed in patients with NASH. The role of hepatic ghrelin in NAFLD requires further research.

  • Thyroid dysfunction (TD) among chronic hepatitis C patients with mild and severe hepatic fibrosis Maribel Rodríguez-Torres, Carlos F. Ríos-Bedoya, Grisell Ortiz-Lasanta, Acisclo M Marxuach-Cuétara, Josselyn Jiménez-Rivera Page 72-77

    Background: Thyroid dysfunction (TD) is associated to chronic hepatitis C (HCV) and interferon (IFN) therapy. The prevalence of TD at baseline and during IFN therapy among stages of hepatic fibrosis is unknown. Goals: To examine the frequency of TD at baseline and during Peg-IFN therapy among patients with severe and mild fibrosis. Study: 100 patients were treated with Peg-IFN and divided in 2 groups (50 each), according to liver histology; Metavir 0-2 (mild fibrosis) and Metavir 3-4 (severe fibrosis). Baseline TD was defined as history of TD, or abnormal thyroid stimulating hormone (TSH) or antiperoxidase thyroid auto-antibodies (TPO -Ab). Frequency of TD during therapy was defined as TD that required treatment. Results: 20% in the severe fibrosis group and 10% in the mild fibrosis group, had TD at baseline. Most of the cases, 31.4% were female as compared to 6.25% males. During therapy, 24% of patients in the severe fibrosis group, compared to 12% in the mild fibrosis, had TD. Most patients had biochemical hypothyroidism, and 66% were female, compared to 33.33 % male. TPO-Ab predicted TD during therapy in 50% of cases while those negative only had 16.6% TD during IFN therapy. Conclusions: Patients with severe fibrosis have more TD events at baseline and during treatment with Peg IFN alfa-2a. Patients with more hepatic fibrosis require careful attention to diagnose and manage TD. More research in the immune mechanisms of hepatic fibrosis progression and autoimmune complications is needed.

EDITORIAL

IMAGES IN HEPATOLOGY

CASE REPORTS

  • Sarcoidosis mimicking primary sclerosing cholangitis requiring liver transplantation Claudio Tombazzi, Bradford Waters, Mohammad K. Ismail, Pamela B. Sylvestre, Antonio Martinez-Hernandez, Caroline A. Riely Page 83-86

    Sarcoidosis is a systemic granulomatous disease of unknown etiology. The association of the cholestatic pattern usually seen in sarcoidosis, with biliary duct changes resembling primary sclerosing cholangitis (PSC) is rare.1 Liver transplantation permits the histological evaluation of the complete explanted liver, making the diagnosis more reliable. In conclusion we present our experience with two patients with sarcoidosis requiring liver transplantation, who presented with clinical and radiological findings characteristics of primary sclerosing cholangitis.

  • Interstitial pneumonitis associated with pegylated interferon alfa-2b therapy for chronic hepatitis C: Case report Raúl Carrillo-Esper, Daniela González-Avila, Marittza Uribe-Ríos, Nahum Méndez-Sánchez Page 87-90

    Since 2004, pegylated interferon (P-IFN) in combination with ribavirin has become the optimal choice of therapy for chronic hepatitis C virus (HCV) infection. IFN α-2b suppresses HCV replication and restores elevated serum aminotransferase levels, leading to improvements in the histological changes in the livers of patients with chronic hepatitis C.1 Unfortunately, P-IFN has several adverse effects, including pneumonitis. This complication has been reported in the treatment of malignant diseases and CHC.2 We report a patient with interstitial pneumonitis thought to be caused by an IFNbased treatment in an unusual scenario of a patient with HCV-related Child–Pugh stage A cirrhosis, who experienced dyspnea, fever, and cough after 12 months of treatment with P-IFN α-2b. Her lung injury and pulmonary symptoms did not disappear despite discontinuation of IFN and the administration of corticosteroid. We concluded that the patient developed a fatal interstitial pneumonitis associated with P-INF α-2b therapy.

  • Pulmonary embolism after sclerotherapy treatment of bleeding varices Syed F. Habib, Raza Muhammad, Anastasios Koulaouzidis, Jaber Gasem Page 91-93

    We describe a case of pulmonary embolism after sclerosant injection for bleeding oesophageal varices. The patient was managed successfully with enoxaparin. Systemic embolization after sclerotherapy is rare and depends upon a number of factors including the amount of sclerosant agent used. The incidence of this complication could be as high as 6% which warrants careful post procedure monitoring of patients.

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