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January - February, 2012

Vol. 11 Issue 1

On the cover: Axial contrast-enhanced CT images at the level of the confluence og the hepatic veins into the hepatic vena cava and liver biopsy at the time of referral when Budd-Chiari syndrome was diagnosed.

HEPATOLOGY HIGHLIGHTS

CONCISE REVIEW

  • Smoking as a risk factor for autoimmune liver disease: what we can learn from primary biliary cirrhosis Daniel S. Smyk, Eirini I. Rigopoulou, Luigi Muratori, Andrew K. Burroughs, Dimitrios P. Bogdanos Page 7-14

    Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterised by the immune-mediated destruction of biliary epithelial cells in small intrahepatic bile ducts. The disease is characterised by circulating anti-mitochondrial antibodies (AMA) as well as disease specific anti-nuclear antibodies (ANA), cholestatic liver biochemistry, and characteristic histology. The disease primarily affects middle-aged females, and its incidence is apparently increasing worldwide. Epidemiological studies have indicated several risk factors for the development of PBC, with family history of PBC, recurrent urinary tract infection, and smoking being the most widely cited. Smoking has been implicated as a risk factor in several autoimmune diseases, including the liver, by complex mechanisms involving the endocrine and immunological systems to name a few. Studies of smoking in liver disease have also shown that smoking may progress the disease towards fibrosis and subsequent cirrhosis. This review will examine the literature surrounding smoking as a risk factor for PBC, as well as a potential factor in the progression of fibrosis in PBC patients.

ORIGINAL ARTICLES

Clinical Studies

Viral Hepatitis
  • Balapiravir plus peginterferon alfa-2a (40KD)/ribavirin in a randomized trial of hepatitis C genotype 1 patients David R. Nelson, Stefan Zeuzem, Pietro Andreone, Peter Ferenci, Robert Herring, Donald M. Jensen, Patrick Marcellin, Paul J. Pockros, Maribel Rodríguez-Torres, Lorenzo Rossaro, Vinod K. Rustgi, Thomas Sepe, Mark Sulkowski, _ Thomason Page 15-31

    Introduction. Balapiravir (R1626, RG1626) is the prodrug of a nucleoside analogue inhibitor of the hepatitis C virus (HCV) RNA-dependent RNA polymerase (R1479, RG1479). This phase 2, double-blind international trial evaluated the optimal treatment regimen of balapiravir plus peginterferon alfa-2a (40KD)/ribavirin. Material and methods. Treatment-naive genotype 1 patients (N = 516) were randomized to one of seven treatment groups in which they received balapiravir 500, 1,000, or 1,500 mg twice daily, peginterferon alfa- 2a (40KD) 180 or 90 μg/week and ribavirin 1,000/1,200 mg/day or peginterferon alfa-2a (40KD)/ribavirin. The planned treatment duration with balapiravir was reduced from 24 to 12 weeks due to safety concerns. Results. The percentage of patients with undetectable HCV RNA was consistently higher in all balapiravir groups from week 2 to 12. However, high rates of dose modifications and discontinuations of one/all study drugs compromised the efficacy assessment and resulted in similar sustained virological response rates in the balapiravir groups (range 32-50%) and the peginterferon alfa-2a (40KD)/ribavirin group (43%). Balapiravir was discontinued for safety reasons in 28-36% of patients (most often for lymphopenia) and the percentage of patients with serious adverse events (especially hematological, infection, ocular events) was dose related. Serious hematological adverse events (particularly neutropenia, lymphopenia) were more common in balapiravir recipients. Two deaths in the balapiravir/peginterferon alfa-2a/ribavirin combination groups were considered possibly related to study medication. Conclusion. Further development of balapiravir for the treatment of chronic hepatitis C has been halted because of the unacceptable benefit to risk ratio revealed in this study (www.ClinicalTrials.gov NCT 00517439).

  • Intrafamilial seropositivity of hepatitis in patients with hepatitis B and C virus in hepatitis clinic in Hamadan, Iran Mitra Ranjbar, Zahra Golzardi, Leila Sedigh, Shahbaz Nekoozadeh Page 32-36

    Objective. To determine intrafamilial seropositivity of HBV and HCV and to compare them in families of infected persons with HBV and HCV in Hamadan clinic of hepatitis. Material and methods. In this analytic cross-sectional study, 651 family members of 200 HBV and HCV infection index cases were entered into the study and after signing an informed consent, they were referred to Blood Transfusion Center. With completion of laboratory tests, interviewers filled the questionnaires. Results. One hundred and eighteen (20.5%) and 107 (18.6%) family members were HBsAg and HBcAb positive respectively. 21 (3.6%) were isolated HBcAb positive. Only one person (1.3%) was HCVAb positive. The general rate of infection in family members of HBV infected people (atleast one case) (49.4%) was significantly higher than that of HCV infected people (3.3%), p < 0.001. Interspouses transmission was evaluated and prevalence of interspouses HBV and HCV infection were 32.3 and 8%, respectively. Conclusion. Intrafamilial and interspousal seropositivity of HBV is obviously more than those of HCV. More attention should be paid to screening and risk lowering activities particularly about HBV infected people and their families.

  • Serum lipids and chronic hepatitis C genotype 4: interaction and significance Mahmoud A. Khattab, Mohammed Eslam, Mayada M. Aly, Mohammed Shatat, Yousef I. Mousa, Hesham Abd-Aalhalim, Hanan Aly, Yehia Shaker Page 37-46

    Background & aim. Metabolic abnormalities are common in chronic hepatitis C infection (CHC). However, the genotypic differences of these disarrangements in patients infected with CHC genotype 4 (HCV-4) and its association with liver histology and viral loads remain unknown. Material and methods. We consecutively enrolled 183 HCV-4 patients and 106 healthy matched controls; to compare metabolic profiles and assess pattern of association of HCV RNA levels as well as histological factors with the serum lipid profile. Results. HCV-4 infection is associated with higher homeostasis model assessment of insulin resistance (HOMA-IR) index, despite that, a favourable lipid pattern, consisting of an elevation in HDL- C and a reduction in serum cholesterol (TC), LDL-C and triglyceride (TG) levels, in comparison with normal matched adults. Significant fibrosis was independently associated with HOMA-IR, portal/periportal inflammation grade, serum cholesterol and age. Univariate association was elucidated between lower LDL-C and TC and Metavir activity score and between higher TG and TC and steatosis. In multivariate analysis, severe hepatitis activity, milder hepatic fibrosis, and triglyceride levels are associated with higher HCV RNA levels. Conclusion. HCV-4 is associated with wide metabolic changes. A proportional relationship is found between serum lipid profiles and hepatitis C viral load and liver histology in patients with HCV-4.

  • Prevalence and resistance pattern of genotype G and H in chronic hepatitis B and HIV co-infected patients in Mexico José Antonio Mata Marín, Carla Ileana Arroyo Anduiza, Gloria María Calderón, Sergio Cazares Rodríguez, José-Luis Fuentes Allen, Rafael Arias Flores, Jesús Gaytán Martínez Page 47-51

    Objective. We estimated the prevalence and identified the resistance pattern of HBV genotypes H and G in HBV monoinfected and HIV co-infected patients. Material and methods. A cross-sectional prevalence and analytic study were performed in chronic hepatitis B patients at the Hospital de Infectología, La Raza National Medical Center in Mexico City. Chronic HBV monoinfected and HIV co-infected patients were included. HBeAg, HBV viral load and genetic analysis of mutations were collected; CD4+ cells count from HIV co-infected patients and HIV RNA were measured. We calculated the prevalence and exact 95% binomial confidence interval and the Odds ratios (OR) with 95% confidence intervals to assess the relationship between the presence of risk factors and HBV genotypes H or G. Results. We enrolled 77 patients, 67 men and 10 women with 37 HIV co-infected patients. The distribution of HBV genotypes was: HBV genotype H 55 (71% [95% CI 60% to 80%]), HBV genotype G 16 (20.7%), HBV genotype F 4 (5.1%) and HBV genotype A 2 (2.6%). The most frequent mutations presented in 8 HIV co-infected patients and one mono-infected patient with antiretroviral therapy (ART) experience were rtM204V and six of them showed genotype G (6/9). Mono-infected HBV patients exposed more probability to HBV genotype H than co-infected HIV patients OR 13.0 (CI 95% 3.40-49.79), p = 0.0001. In contrast co-infected patients presented less possibility to have genotype H, 0.56 (CI 95% 0.42-0.75). Conclusions. This study confirms the high prevalence of HBV genotype H in Mexico; furthermore, our results suggest that HBV genotype G predominates in co-infected patients. As well, rtM204V and rtL180M mutations are common in HBV-HIV co-infected patients with genotype G and ART experience.

  • Re-treatment of previous non-responders and relapsers to interferon plus ribavirin with peginterferon alfa-2a (40KD), ribavirin ± amantadine in patients with chronic hepatitis C: randomized multicentre clinical trial Mario G. Pessôa, Hugo Cheinquer, Paulo R.L. Almeida, Giovanni F. Silva, Maria Patelli J.S. Lima, Raymundo Paraná, Marco A. Lacerda, Edison R. Parise, José R.B. Pernambuco, Suelene S. Pedrosa, Rosângela Teixeira, Hoel Sette Jr., Fernando Tatsch Page 52-61

    Introduction. A large number of patients with chronic hepatitis C have not been cured with interferon-based therapy. Therefore, we evaluated the efficacy of amantadine combined with the standard of care (pegylated interferon plus ribavirin) in patients who had not responded to or had relapsed after ≥ 24 weeks of treatment with conventional interferon plus ribavirin. Material and methods. Patients stratified by previous response (i.e., non-response or relapse) were randomized to 48 weeks of open-label treatment with peginterferon alfa-2a (40KD) 180 μg/week plus ribavirin 1,000/1,200 mg/day plus amantadine 200 mg/ day (triple therapy), or the standard of care (peginterferon alfa-2a [40KD] plus ribavirin). Results. The primary outcome was sustained virological response (SVR), defined as undetectable hepatitis C virus RNA in serum (< 50 IU/mL) at end of follow-up (week 72). Among patients with a previous non-response, 12/53 (22.6%; 95% confidence interval [CI] 12.3-36.2%) randomized to triple therapy achieved an SVR compared with 16/52 (30.8%; 95% CI 18.7-45.1%) randomized to the standard of care. Among patients with a previous relapse 22/39 (56.4%; 95% CI 39.6–72.2%) randomized to triple therapy achieved an SVR compared with 23/38 (60.5%; 95% CI 43.4-76.0%) randomized to the standard of care. Undetectable HCV RNA (< 50 IU/mL) at week 12 had a high positive predictive value for SVR. A substantial proportion of non-responders and relapsers to conventional interferon plus ribavirin achieve an SVR when re-treated with peginterferon alfa-2a (40KD) plus ribavirin. Conclusion. Amantadine does not enhance SVR rates in previously treated patients with chronic hepatitis C and cannot be recommended in this setting.

Liver transplantation
  • Region 11 MELD Na exception prospective study Robert A. Fisher, Douglas M. Heuman, Ann M. Harper, Martha K. Behnke, Alastair D. Smith, Mark W. Russo, Steven Zacks, John W. McGillicuddy, James Eason, Michael K. Porayko, Patrick Northup, Michael R. Marvin, Johnathan Hundley, _ Nair Page 62-67

    Introduction. Hyponatremia complicates cirrhosis and predicts short term mortality, including adverse outcomes before and after liver transplantation. Material and methods. From April 1, 2008, through April 2, 2010, all adult candidates for primary liver transplantation with cirrhosis, listed in Region 11 with hyponatremia, were eligible for sodium (Na) exception. Results. Patients with serum sodium (SNa) less than 130 mg/dL, measured two weeks apart and within 30 days of Model for End Stage Liver Disease (MELD) exception request, were given preapproved Na exception. MELD Na was calculated [MELD + 1.59 (135-SNa/30 days)]. MELD Na was capped at 22, and subject to standard adult recertification schedule. On data end of follow-up, December 28, 2010, 15,285 potential U.S. liver recipients met the inclusion criteria of true MELD between 6 and 22. In Region 11, 1,198 of total eligible liver recipients were listed. Sixty-two (5.2%) patients were eligible for Na exception (MELD Na); 823 patients (68.7%) were listed with standard MELD (SMELD); and 313 patients (26.1%) received HCC MELD exception. Ninety percent of MELD Na patients and 97% of HCC MELD patients were transplanted at end of follow up, compared to 49% of Region 11 standard MELD and 40% of U.S.A. standard MELD (USA MELD) patients (p < 0.001); with comparable dropout rates (6.5, 1.6, 6.9, 9% respectively; p = 0.2). MELD Na, HCC MELD, Region 11 SMELD, and USA MELD post-transplant six-month actual patient survivals were similar (92.9, 92.8, 92.2, and 93.9 %, respectively). Conclusion. The Region 11 MELD Na exception prospective trial improved hyponatremic cirrhotic patient access to transplant equitably, and without compromising transplant efficacy.

Non alcoholic fatty liver disease (NAFLD)
  • Serum homocysteine levels in patients with nonalcoholic fatty liver disease Stergios A. Polyzos, Jannis Kountouras, Kalliopi Patsiaoura, Evangelia Katsiki, Efthimia Zafeiriadou, Georgia Deretzi, Christos Zavos, Emmanouel Gavalas, Panagiotis Katsinelos, Vasileia Mane, Aristidis Slavakis Page 68-76

    Background and rational for the study. Nonalcoholic fatty liver disease (NAFLD) is regarded as the hepatic component of insulin resistance (IR) syndrome, but data on serum homocysteine (HCY) are limited. The aim of the study was the evaluation of serum HCY levels in patients with NAFLD. Material and methods. Thirty-one patients (54 ± 11 years, 8 males) with biopsy-proven NAFLD, 15 with simple nonalcoholic fatty liver (NAFL) and 16 with nonalcoholic steatohepatitis (NASH), and 22 healthy controls (52 ± 9 years, 5 males) matched for gender, age and body mass index (BMI), were recruited. Blood samples for HCY, folate, vitamin B12, insulin and standard biochemical tests were obtained after overnight fasting. Homeostatic model of assessment-insulin resistance (HOMA-IR) was calculated. Results. There was no difference in mean serum HCY levels between controls and NAFLD patients (12.6 ± 4.6 vs. 13.5 ± 2.6 mmol/L, respectively; p = 0.432). Serum folate and vitamin B12 were also similar between the study groups. Mean age, BMI, serum folate and vitamin B12 did not differ between NAFL and NASH patients. However, when compared with NAFL patients, NASH patients had lower mean serum HCY levels (12.3 ± 2.5 vs. 14.7 ± 2.1 mmol/L; p = 0.006). HCY was lower by increasing the grading of fibrosis (p = 0.005), portal inflammation (p = 0.029) and steatosis location (p = 0.021). In logistic regression analysis, HCY independently predicted NASH (p = 0.045) after adjustment for gender, age, BMI, AST, glucose and HOMA-IR. Conclusion. Our data suggest that serum HCY levels are lower in NASH compared with NAFL patients and can independently predict NASH. Serum HCY might represent another non-invasive marker for the assessment of NAFLD.

Miscellaneous
  • Room-temperature susceptometry predicts biopsy-determined hepatic iron in patients with elevated serum ferritin Bryan D. Maliken, William F. Avrin, James E. Nelson, Jody Mooney, Sankaran Kumar, Kris V. Kowdley Page 77-84

    Background. There is an ongoing clinical need for novel methods to measure hepatic iron content (HIC) noninvasively. Both magnetic resonance imaging (MRI) and superconducting quantum interference device (SQUID) methods have previously shown promise for estimation of HIC, but these methods can be expensive and are not widely available. Room-temperature susceptometry (RTS) represents an inexpensive alternative and was previously found to be strongly correlated with HIC estimated by SQUID measurements among patients with transfusional iron overload related to thalassemia. Aim. The goal of the current study was to examine the relationship between RTS and biochemical HIC measured in liver biopsy specimens in a more varied patient cohort. Material and methods. Susceptometry was performed in a diverse group of patients with hyperferritinemia due to hereditary hemochromatosis (HHC) (n = 2), secondary iron overload (n = 3), nonalcoholic fatty liver disease (NAFLD) (n = 2), and chronic viral hepatitis (n = 3) within one month of liver biopsy in the absence of iron depletion therapy. Results. The correlation coefficient between HIC estimated by susceptometry and by biochemical iron measurement in liver tissue was 0.71 (p = 0.022). Variance between liver iron measurement and susceptometry measurement was primarily related to reliance on the patient's body-mass index (BMI) to estimate the magnetic susceptibility of tissue overlying the liver. Conclusions. We believe RTS holds promise for noninvasive measurement of HIC. Improved measurement techniques, including more accurate overlayer correction, may further improve the accuracy of liver susceptometry in patients with liver disease.

  • Association between cholecystectomy for gallstone disease and risk factors for cardiovascular disease Norberto C. Chávez Tapia, Ileana Mac Kinney-Novelo, Sergio E. Sifuentes-Rentería, Maximiliano Torres-Zavala, Gildardo Castro-Gastelum, Karla Sánchez-Lara, Carla Paulin-Saucedo, Misael Uribe, Nahum Méndez-Sánchez Page 85-89

    Objective. Gallbladder disease and cardiovascular disease share risk factors. Both have a great impact on the economics of health systems. There is evidence suggesting an increased risk of cardiovascular disease in patients with gallbladder disease, but the association of gallbladder disease with other risk factors for cardiovascular disease is unclear. The aim of this study is to analyse the relationship between cholecystectomy for gallstone disease and risk factors for cardiovascular disease. Material and methods. This is a case-control study comparing subjects undergoing cholecystectomy with controls without gallbladder disease or cholecystectomy. Demographic, anthropometric, and biochemical data were recorded and risk factors for cardiovascular disease were assessed. The data were analysed with chi square test, student t test and logistic regression (univariate and multivariate). Results. Seven hundred and ninety-eight subjects were included. The multivariate analyses demonstrated that, compared with controls, cases had an increased prevalence of metabolic risk factors for cardiovascular disease (odds ratio (OR) 2.8, 95% confidence interval (CI) 1.8-4.8, p = 0.001), including type 2 diabetes mellitus (OR 2.2, 95% CI 1.1-4.5, p = 0.018), high blood pressure (OR 5.1, 95% CI 2.6-10.1, p = 0.001), and high cholesterol levels (OR 2.7, 95% CI 1.3-5.5, p = 0.004). No differences were observed in the incidence of cardiovascular disease. Conclusion. Patients undergoing cholecystectomy had an increased prevalence of risk factors for cardiovascular disease, independent of age, sex, or body mass index.

  • Causes of renal failure in patients with decompensated cirrhosis and its impact in hospital mortality Grazielle Cerqueira de Carvalho, Catarina de Andrade Regis, Jamile Rosário Kalil, Liv Aparício Cerqueira, Daniel Silva Barbosa, Marina Pamponet Motta, Marília da Silva Nery, Maria Alice Pires Soares, Claudio Celestino Zollinger, Paulo Lisboa Bittencourt Page 90-95

    Background. Renal failure (RF) is reported to occur in 11-49% of the patients with decompensated end-stage liver disease (ESLD) and has been associated with increased mortality, particularly in the occurrence of hepatorenal syndrome (HRS) type 1. Aims. To evaluate the frequency and outcome of RF in patients admitted to the hospital due to decompensated ESLD and to assess the impact of the underlying cause of RF on survival. Material and methods. Four hundred and six patients (65% males, mean age 62 ± 12 years) with decompensated ESLD were evaluated for the occurrence of RF (defined as serum creatinine ³ 1.5 mg/mL). The underlying cause of RF was reckoned in each subject and compared to outcome. Results. Renal failure was observed in 39% of the patients at admission and in 10% of the subjects during hospitalization. Mortality was significantly higher in subjects with RF (26 vs. 1%, p < 0.000001). Hypovolemia, bacterial infections, parenchymal kidney diseases and HRS were identified as causes of RF in, respectively, 40, 32, 15 and 12% of the cases. Mortality was significantly higher in those subjects with HRS type 1 and bacterial infections, when compared to other causes of RF. Conclusions. Renal failure occurs in nearly half of the patients with decompensated ESLD. It is most commonly caused by hypovolemia and bacterial infections. Occurrence of RF has an adverse impact in patient survival, particularly in those subjects with bacterial infections and HRS type 1, prone to develop progressive renal dysfunction despite intensive medical care.

  • Hepatic dysfunction in children with tuberculosis on treatment with antituberculous therapy Sasha Mansukhani, Ira Shah Page 96-99

    Aim. To determine the incidence and factors associated with drug induced hepatic dysfunction in children on anti-tuberculous treatment (ATT). Setting. Pediatric Tuberculosis Clinic at B.J. Wadia Children's Hospital, Mumbai. Material and methods. 46 children with tuberculosis on ATT between April 2007 and February 2008 were included. Serum glutamic pyruvic transaminase (SGPT) level was measured at the beginning, after 15 days of starting ATT, at the end intensive phase and then if the patient developed symptoms of hepatic dysfunction. A value 3 times the normal value of the testing laboratory was considered to be significant for liver dysfunction. Liver dysfunction was analysed for association with factors like age, sex, weight, malnutrition, type of tuberculosis and severity of tuberculosis using SPSS Statistics software, Version15.0. Results. Seven (15.2 %) out of 46 children developed drug induced hepatic dysfunction, of which 2 (28.6%) patients had 2 episodes of liver dysfunction while 5 (71.4%) had 1 episode of liver dysfunction. One (14.3%) developed symptom of hepatitis in the form of jaundice and hepatomegaly. All the patients developing liver dysfunction were in the intensive phase of treatment. The mean age of the children developing liver dysfunction was 4.0 ± 3.76 years. Liver dysfunction was associated with age younger than 3½ years (p = 0.025). Liver dysfunction was not associated with sex, weight, malnutrition, type of tuberculosis and severity of tuberculosis. Conclusion. Regular monitoring of SGPT levels is recommended in all children on ATT below the age of 3 ½ years.

  • Effect of cirrhosis at baseline on the outcome of type 1 autoimmune hepatiti Graciela Landeira, Silvia Morise, Eduardo Fassio, Margarita Ramonet, Estela Álvarez, Patricia Caglio, Cristina Longo, Nora Domínguez Page 100-106

    Material and methods. With the aim of analyzing the influence of presence of cirrhosis at baseline on the outcome, we revised the evolution of a cohort of patients with type 1 autoimmune hepatitis, prospectively followed at a single hospital. 139 patients (113 females, 26 males), median age 45.7 years, interquartile range 13-59 years, were followed-up for a median period of 58 months (interquartile range 27-106). Results. At baseline, 55 patients had cirrhosis and they were significantly older, had lower prothrombin activity and serum albumin than patients without cirrhosis. In contrast, patients without cirrhosis had significantly higher bilirubin, AST and ALT levels at diagnosis time. There was no significant difference in the follow-up time between patients with and without cirrhosis at baseline and either in the percentage of patients receiving immunosupresor treatment (80 vs. 91%, respectively) or in the response to therapy (complete response in 82 vs. 95%, respectively). However, patients with cirrhosis had a significantly lower probability of remaining free of cirrhosis complications (49.1% at 102 months, 95%CI, 35.5-67.9% vs. 86.7%, 95%CI, 77.1%- 97.5%, respectively) (p = 0.0000) and a significantly lower overall survival at 120 months (67.1%, 95%CI, 51.3- 87.6 vs. 94.4%, 95%CI, 86.9-100%, respectively) (p = 0.003) than those without cirrhosis at presentation. Conclusion. Patients with type 1 autoimmune hepatitis and cirrhosis at presentation have a lower survival than those without cirrhosis despite a similar response to treatment.

Basic studies

  • Amoebic liver abscess production by Entamoeba dispar Silvio S. Dolabella, Jesús Serrano-Luna, Fernando Navarro-García, René Cerritos, Cecilia Ximénez, José Manuel Galván-Moroyoqui, Edward F. Silva, Victor Tsutsumi, Mineko Shibayama Page 107-117

    Although Entamoeba dispar displays a similar morphology to Entamoeba histolytica, cellular and molecular studies have revealed significant differences between these two amoebae, including the former being characterized as non-pathogenic and the later as pathogenic. However, recent in vivo and in vitro experiments have shown that E. dispar strains of different origin are capable of causing liver damage and destroying cell culture lines in the presence of common intestinal bacteria. These results suggested that E. dispar may present pathogenic behavior according to the specific E. dispar strain, culture and environmental conditions. To investigate this possibility, we carried out in vivo and in vitro studies using a xenic strain E. dispar (ICB-ADO) isolated from a symptomatic non-dysenteric Brazilian patient. This strain was able to induce liver necrosis in a hamster model that was more severe than that produced by E. histolytica. The ICB-ADO isolate also caused significantly more destruction of cultured MDCK cells and increased loss of transepithelial resistance than did the E. histolytica. Xenic E. dispar exhibited high proteolytic activity, which was partially inhibited by the addition of cysteine-protease inhibitors. Based on our biochemical and molecular characterization of E. dispar (ICB-ADO) xenic culture and its ability to produce liver abscesses, we conclude that this specific strain can indeed produce tissue damage, distinct from the frequently used non- pathogenic E. dispar SAW 760 strain.

  • Cytokines as important playmakers of experimental hepatocarcinogenesis confounded by diabetes Nabil M. Abdel-Hamid, Maiiada H. Nazmy, Manal I. Abdel-Ghany, Walaa H. Nazmy Page 118-127

    Purpose. To explore the possible intermediary pathways through which diabetes mellitus (DM) adversely worsens hepatocellular carcinoma (HCC), focusing on cell life controllers as some transcription factors and inflammatory mediators. Material and methods. Forty male albino rats were divided into four groups, control, cancer [given single intra-peritoneal (IP) dose of diethyl nitrosamine, NDEA, 125 mg/kg body weight], diabetic (given single dose of streptozotocin, STZ, 65 mg/kg) and cancer diabetic. HCC was initiated with NDEA, 3 weeks later, DM was induced with STZ. At 14th week, animals were sacrificed. Serum ALT, AST, GGT activities, AFP, IL-6, TNF-α levels and liver tissue Bax and Bcl2 proteins were measured. Liver sections were stained for histological examination. Both histological and AFP variations were chosen to prove cancer development. Results. NDEA group showed significant increase in liver weight, serum ALT, AST, GGT, AFP, TNF-α, IL-6 and liver Bcl2 protein with decrease in total body weight, liver Bax protein and Bax/Bcl2 ratio. These effects were more pronounced in DENA plus STZ group. IL-6, TNF-α and Bcl2 were positively correlated while Bax and Bax/Bcl2 ratio were negatively correlated to AFP levels reflecting potential diagnostic value. Conclusion. Co-induction of DM in the course of hepatocarcinogenesis can dramatically influence disease progression through inflammation and retarded apoptosis. The suggested apoptotic and inflammatory markers seem to be beneficial diagnostic tools for HCC and improve the diagnostic performance of AFP.

IMAGES IN HEPATOLOGY

  • Glisson´s capsule blistering after hyperthermic intraperitoneal chemotherapy Heriberto Medina-Franco, Daniel Zamora-Valdés, Ariadne Sánchez-Ramón, Gabriela Trejo-Gómez Page 128-129

    Hypertermic intraperitoneal chemotherapy is a treatment option after cytorreduction of certain types of malignancies with peritoneal spread. Blistering of the Glisson's capsule has not been previously reported as a consequence of this treatment modality. Patient do not experiment any associated morbidity.

CASE REPORTS

  • Abnormal liver function tests in a patient with myotonic dystrophy type 1 Maria Kalafateli, Christos Triantos, Athanasios Tsamandas, Gerasimos Kounadis, Chryssoula Labropoulou-Karatza Page 130-133

    Myotonic dystrophy type 1, also known as Steinert's disease, is a multisystemic disorder with significant genetic and clinical heterogeneity. Apart from skeletal muscles' myotonia and wasting, a variety of system organs can be affected. We report on a 49 years old female patient with unremarkable medical and family history, who presented with elevated liver enzymes without signs or symptoms of chronic liver disease neither neurological features. Initial assessment, including liver biopsy, did not reveal the cause of these abnormalities. Eight months later, she complained for disequilibrium and eventually electromyography confirmed the diagnosis of Steinert's disease. Steinert's disease should be considered in the differential diagnosis of patients with elevated liver enzymes, as long as abnormal liver tests may be the initial presentation. The pathophysiological mechanism of this abnormality remains unclear.

  • An unusual cause of cancer mimicry following liver transplantation Karim Qumosani, Natasha Chandok Page 134-137

    Sirolimus is an approved anti-rejection agent following liver or kidney transplantation that works through inhibition of the mammalian target of rapamycin (mTOR). As sirolimus functions through a pathway independent of calcineurin inhibition, it may have less potential for nephrotoxicity and carcinogenesis. That being said, there are a myriad of potential adverse effects reported with sirolimus, many of which are severe and unknown or poorly understood. Herein we present a case of sirolimus causing a serious but uncommon adverse event in an adult liver transplant recipient; the adverse event in this instance unfortunately resulted in significant medical testing and morbidity. The adverse event profile of sirolimus is summarized through review of available evidence.

  • Acute liver failure due to non-exertional heatstroke after sauna Elife Erarslan, Ilhami Yüksel, Serap Haznedaroglu Page 138-142

    Acute liver failure is defined as rapid loss of liver function that patients without previously recognized liver disease sustain a liver damage. Acute liver failure due to non-exertional heatstroke has rarely been reported. We reported here an unusual case of heat stroke induced acute liver failure (ALF) after sauna. A 63 year old man without previously recognized liver and other systemic disease was admitted for loss of consciousness and impaired liver function after sauna. Despite intensive supportive care, ALF developed. Liver transplantation was planned but the patient died on the sixth day of hospitalization. Non-exertional heatstroke induced ALF is a rare and serious condition. ALF caused by non-exertional heatstroke which requires liver transplantation for definitive solution should be kept in mind in early period.

LETTER TO EDITOR

LIVER NEWS ELSEWHERE

  • Intestinal nuclear bile acid receptor FXR and cholestasis Jorge A. López-Velázquez, Ibrahim G. Castro-Torres, Vicente Sánchez-Valle, Nahum Méndez-Sánchez Page 152-154

    Background & aims. Cholestasis is a liver disorder characterized by impaired bile flow, reduction of bile acids (BA) in the intestine, and retention of BAs in the liver. The farnesoid X receptor (FXR) is the transcriptional regulator of BA homeostasis. Activation of FXR by BAs reduces circulating BA levels in a feedback mechanism, repressing hepatic cholesterol 7a-hydroxylase, the rate-limiting enzyme for the conversion of cholesterol to BA. This mechanism involves the hepatic nuclear receptor small heterodimer partner and the intestinal fibroblast growth factor (FGF) 19 and 15. We investigated the role of activation of intestine-specific FXR in reducing hepatic levels of BA and protecting the liver from cholestasis in mice. Methods. We generated transgenic mice that express a constitutively active FXR in the intestine. Using FXR gain- and loss-offunction models, we studied the roles of intestinal FXR in mice with intrahepatic and extrahepatic cholestasis. Results. Selective activation of intestinal FXR induced FGF15 and repressed hepatic Cyp7a1, reducing the pool size of BA and changing the BA pool composition. Activation of intestinal FXR protected mice from obstructive extrahepatic cholestasis following bile-duct ligation or administration of anaphthylisothiocyanate. In Mdr2-/- mice, transgenic expression of activated FXR in the intestine protected against liver damage, whereas absence of FXR promoted progression of liver disease. Conclusions. Activation of FXR transcription in the intestine protects the liver from cholestasis in mice by inducing FGF15 expression and reducing the hepatic pool of BA; this approach might be developed to reverse cholestasis in patients. Abstract published under permission of Elsevier provided by Copyright Clearence Center.

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