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May - June, 2014

Vol. 13 Issue 3

On the cover: Peripheral blood smear demonstrate poilikocytosis and abundant acanthocytes or spur cells and B. Abdominal MRI shows homogeneous hypointense signal of the liver and pancreas.

HEPATOLOGY HIGHLIGHTS

CONCISE REVIEW

  • Combined hepatocellular-cholangiocarcinoma (cHCC-CC): a distinct entity Kate O’Connor, Joanna C. Walsh, David F. Schaeffer Page 317-322

    Patients with hepatocellular carcinoma (HCC), the fifth most common cancer worldwide, display a highly variable clinical course, suggesting that HCC encompasses several biologically distinct subtypes. This heterogeneity has the potential to impede both treatment decisions and prognostic predictions for patients with HCC. One distinct, albeit rare, subtype of HCC is combined hepatocellular-cholangiocarcinoma (cHCC-CC), which overall carries a poorer prognosis than HCC and cholangiocarcinoma (CC) alone. This review discusses predominantly the histopathologic and pathogenetic intricacies of this tumor and highlights the need for an accurate diagnosis of this specific HCC subtype.

  • An update on management of Budd-Chiari syndrome Andrea Mancuso Page 323-326

    The topic of this paper is to report an update on management of Budd-Chiari syndrome (BCS). Actually, the flow-chart of BCS management comes from experts opinion and is not evidence-based due to the rarity of BCS. Management of BCS follows a step-wise strategy. Anticoagulation and medical therapy should be the first line treatment. Revascularization or TIPS in case of no response to medical therapy. OLT as a rescue therapy. Surgery has limited but important space, especially in cases with high inferior vena cava obstruction not suitable for endovascular treatment. However, no clear indication can actually be given about the timing of different treatments. Moreover, there is some concern about treatment of some subgroup of patients, especially regarding the risk of recurrence after liver transplantation. This paper propose a new algorithm of BCS management suggesting an earlier therapeutic approach when clinical signs are evident.

ORIGINAL ARTICLES

Clinical Studies

Viral Hepatitis
  • Efficacy and safety of long term entecavir in chronic hepatitis B treatment naïve patients in clinical practice Ezequiel Ridruejo, Sebastián Marciano, Omar Galdame, María V. Reggiardo, Alberto E. Muñoz, Raúl Adrover, Daniel Cocozzella, Nora Fernández, Claudio Estepo, Manuel Mendizabal, Gustavo A. Romero, Diana Levi, Teresa Schroder, Silvia Paz, Hugo Fainboim, Oscar G. Mandó, Adrián C. Gadano, Marcelo O. Silva Page 327-336

    Background and aims. Entecavir (ETV) is effective and safe in patients with chronic hepatitis B in the short term, but its long term efficacy and safety has not been established. Material and methods. We evaluated HBV DNA clearance, HBeAg/antiHBe and HBsAg/antiHBs seroconversion rates in HBeAg-positive and negative NUC naïve HBV patients treated with ETV for more than 6 months, and predictors of response. Results. A hundred and sixty nine consecutive patients were treated with ETV for a median of 181 weeks. 61% were HBeAg positive, 23% were cirrhotics, and mean HBV-DNA levels were 6,88 ± 1,74 log IU/mL. Overall, 156 (92%) patients became HBV DNA undetectable, 92 (88%) HBeAg positive and 64 (98%) HBeAg negative patients. Seventy four (71%) patients cleared HBeAg after a median of 48 weeks of treatment, 23 (14%) patients cleared HBsAg (19 HBeAg positive and 4 HBeAg negative, p 0.025) after a median of 96 weeks of treatment, and 22 (13%) patients developed protective titers of anti-HBs. At the end of the study, 35 (20%) patients had discontinued therapy: 33 HBeAg positive and 2 HBeAg negative; 9 of them (26%) developed virological relapse after a median of 48 weeks of stopping treatment. None of the patients had primary non response and one patient developed breakthrough. Two patients developed HCC, three underwent liver transplantation and 3 deaths were attributable to liver-related events. No serious adverse events were reported. Conclusion. Long term ETV treatment showed high virological response rates, and a favorable safety profile for NUC-naive HBeAg-positive and negative patients treated in clinical practice.

  • Comparison of two diagnostic algorithms for the identification of patients with HCV viremia using a new HCV Antigen test Miguel Ángel Reyes-Méndez, Luis Juárez-Figueroa, Patricia Iracheta-Hernández, Yasmín Medina-Islas, Verónica Ruiz-González Page 337-342

    Background. Patients exposed to hepatitis C virus (HCV) may develop chronic infection with viremia. The diagnosis of this condition requires the use of several laboratory tests in algorithms tailored to the population and resources available for each laboratory. Aim. We compared the diagnostic efficacy of two diagnostic algorithms for the identification of viremic patients with HCV. One based on confirmation of reactive antibody results with molecular techniques (reverse transcription polymerase chain reaction, RTPCR) and the other based on the use of a new HCV core antigen test (HCV Ag). Material and methods. We measured levels of anti-HCV, HCV Ag and viral load (trough RT-PCR) in parallel, in 211 samples (53 antibody positive, 158 antibody negative). Using the three results available for each sample we simulated the diagnostic performance of the two algorithms and compared them to the results of RT-PCR as gold standard. Results. Both algorithms showed a high degree of concordance for viremic patients. The percentage of correctly classified patients was 99.05% for the algorithm based on RT-PCR and 98.10% for the HCV Ag algorithm. The HCV core Ag test showed a clinical sensitivity of 0.917 and showed a good correlation to the results of molecular biology. Spearman rank correlation coefficient (ρ) of 0.97 (95% CI 0.95 to 0.99, p < 0.0001). Conclusion. An algorithm incorporating HCV Ag as confirmatory test for anti-HCV results is a feasible alternative to the use of molecular techniques in laboratories that do not have access to them or require faster turn around times.

  • Treatment with Metadoxine and its impact on early mortality in patients with severe alcoholic hepatitis Fátima Higuera-de la Tijera, Alfredo I. Servín-Caamaño, Javier Cruz-Herrera, Aurora E. Serralde-Zúñiga, Juan M. Abdo-Francis, Gabriela Gutiérrez-Reyes, José L. Pérez-Hernández Page 343-352

    Background & Aim. Despite treatment with glucocorticoids, mortality remains high in patients with severe alcoholic hepatitis. Oxidative stress and depletion of mitochondrial glutathione are implicated factors in liver injury. The aim of this study was to evaluate the impact of the addition of metadoxine, a drug which possesses a multifactorial mechanism of action, including antioxidant properties, to standard treatment with glucocorticoids in patients with severe alcoholic hepatitis. Material and methods. This randomized open label clinical trial was performed in Mexico’s General Hospital (Registry Key DIC/10/107/03/043). We randomized 70 patients with severe alcoholic hepatitis. The first group received prednisone (40 mg/day), and the second group received prednisone (40 mg/day) plus metadoxine tablets (500 mg three times daily). The duration of treatment in both groups was 30 days. Survival at 30 and 90 days, development of complications, adverse events and response to treatment (Lille model) were assessed. Results. In the group receiving metadoxine, significant improvements were observed, as follows: survival at 30 days (74.3 vs. 45.7%, P = 0.02); survival at 90 days (68.6 vs. 20.0%, P = 0.0001). There was less development or progression of encephalopathy (28.6 vs. 60.0%, P = 0.008) and hepatorenal syndrome (31.4 vs. 54.3%, P = 0.05), and the response to treatment (Lille model) was higher in the metadoxine group (0.38 vs. 0.63, P = 0.001; 95% CI 0.11 to 0.40). There were no differences between groups regarding the development or progression of variceal hemorrhage or infection. The incidence of adverse events, mainly gastrointestinal, was similar in both groups. Conclusions. Addition of metadoxine to glucocorticoid treatment improves the short-term survival of patients with severe alcoholic hepatitis and diminishes the development or progression of encephalopathy and hepatorenal syndrome.

Non alcoholic fatty liver disease (NAFLD)
  • Inflammation is not the cause of an elevated serum ferritin in non-alcoholic fatty liver disease Melanie D. Beaton, Subrata Chakrabarti, Paul C. Adams Page 353-356

    Background. In non-alcoholic fatty liver disease (NALFD), it has often been assumed that an elevation in serum ferritin is likely related to inflammation rather than iron overload. Material and methods. Patients referred with NAFLD were entered into a clinical study of phlebotomy therapy. A liver biopsy with liver iron concentration was done at entry and 6 months after phlebotomy (n = 56) until the patient had a low serum ferritin or developed anemia. Serum ferritin was compared to liver iron concentration, ESR, CRP, BMI and grade of inflammation on liver biopsy. Results. Iron removed by phlebotomy in NAFLD correlated with the decrease in serum ferritin (r = 0.57, p = 0.0014) and liver iron concentration (r = 0.57, p = 0.0013). There was no significant correlations between serum ferritin and ESR, CRP or grade of liver inflammation. Conclusions. Serum ferritin is related to liver iron storage in NAFLD and decreasing body iron stores by phlebotomy is reflected by an appropriate decrease in serum ferritin. Inflammation is not the cause of the elevated serum ferritin in fatty liver disease.

Miscellaneous
  • Evaluation of tumor markers for the differential diagnosis of benign and malignant ascites Fang Liu, Xinjuan Kong, Qian Dou, Jin Ye, Dong Xu, Haitao Shang, Keshu Xu, Yuhu Song Page 357-363

    Introduction. The diagnosis of malignant ascites is a challenging problem in clinical practice, non-invasive techniques should be developed to improve diagnostic accuracy. The diagnostic performances of tumor markers in malignant ascites remained unsettled. Our aim was to evaluate diagnostic performance of tumor markers in differential diagnosis of benign and malignant ascites. Material and methods. A total of 437 patients were enrolled, and the relevant parameters of the patients were analyzed for the differentiation of benign ascites from malignant ascites. Results. At the predetermined cutoff values of tumor makers, tumor markers in ascitic fluid showed better diagnostic performance than those in serum. Combined use of tumor markers and the cytology increased the diagnostic yield of the latter by 37%. In cytologically negative malignant ascites, tumor markers provided assistance in differentiating malignant ascites from benign ascites, and the combination of ascitic tumor markers yielded 86% sensitivity, 97% specificity. Conclusion. Use of a panel of tumor markers exhibited excellent diagnostic performance in diagnosing malignant ascites, which indicated the detection of tumor markers may represent a beneficial adjunct to cytology, thus guiding the selection of patients who might benefit from further invasive procedures.

  • The effect of bacterial infections in cirrhotic patients with esophageal variceal bleeding Zuo-Hua Gan, Chen-Chi Tsai, Kuo-Chih Tseng, Chih-Chun Tsai, Yu-Hsi Hsieh, Tsung-Hsing Hung Page 364-369

    Background. Cirrhotic patients are prone to having bacterial infections due to impaired innate immunity. This nationwide population-based study aimed to identify the effect of bacterial infections on the mortality of the cirrhotic patients with esophageal variceal bleeding (EVB). Material and methods. The Taiwan National Health Insurance Database was used to collect data about the cirrhotic patients receiving endoscopic procedures for EVB between January 1, 2004 and December 31, 2004. The enrolled patients were followed up individually for one year to identify their 6-week and 1-year mortalities. Results. Of the 2,053 cirrhotic patients with EVB, 318 (15.5 %) were diagnosed with bacterial infections. Compared to non-infection group, the adjusted hazard rations (HRs) of bacterial infection for 6-week and 1-year mortalities were 2.69 (2.06-3.52) and 1.89 (1.56-2.28), respectively. Compared to non-infection group, the HRs of pneumonia, spontaneous bacterial peritonitis, urinary tract infection, and sepsis without specific focus (SWSF) were 3.54, 1.91, 1.04, and 3.95 for 6-week mortality, and 3.18, 1.52, 1.15, and 2.23 for 1-year mortality of cirrhotic patients with EVB. Conclusions. In cirrhotic patients with EVB, bacterial infections increase 2.7 folds of 6-week mortality and 1.9 folds of 1-year mortality. Of all infections, pneumonia and SWSF contributed higher risks for mortality.

  • Antioxidant effect of N-acetylcysteine on prehepatic portal hypertensive gastropathy in rats Francielli Licks, Camila Marques, Cláudio Zetler, Maria I. Morgan Martins, Cláudio A. Marroni, Norma P. Marroni Page 370-377

    Background. Portal hypertension is a clinical syndrome associated with the development of a hyperdynamic circulation and gastroesophageal varices. Aim. To evaluate the antioxidant effect of N-acetylcysteine on portal hypertensive rats. Material and methods. Portal hypertension was induced by partial portal vein ligation (PPVL). Oxidative damage in the stomach was measured by lipoperoxidation trough thiobarbituric acid reactive substances (TBARS) and antioxidant enzyme activity; we also evaluated nitrates and nitrites level and histology stained by hematoxylin-eosin. We performed evaluation of portal pressure and measurement of vessels diameter. Liver damage was evaluated by measuring hepatic enzymes. The animals were divided in four experimental groups (n = 6): Sham-operated (SO), SO + NAC, Partial portal vein ligation (PPVL) and PPVL + NAC. N-acetylcysteine (10 mg/kg ip) was administered daily for 7 days and started 8 days after surgery. Results. The portal hypertensive group showed an increase in portal pressure, vessels diameter, levels of TBARS and nitrates and nitrites when compared to SO group. These values were accompanied by a decrease in superoxide dismutase (SOD) and glutathione peroxidase (GPx) antioxidant enzyme activity. Histology showed dilated vessels in the gastric mucosa in the PPVL group. NAC was able to decrease portal pressure values, vessels diameter, TBARS and also nitrates and nitrites levels when compared to PPVL group. Furthermore, PPVL+NAC group presented an increase in SOD and GPx activity. N-acetylcysteine attenuated damage in gastric mucosa. Conclusion. Oxidative stress is associated with portal hypertension and that antioxidant NAC is able to minimize damages of PPVL in rats.

  • Capsulorrhaphy in the management of liver hydatid cyst Samad Mosaddeghi K., Hengameh K. Heris, Amrollah Bayat, Zahra Mosaddeghi K. Page 378-383

    Introduction. Hydatid disease is a major health problem in some parts of the world. There are several nonoperative and operative ways to treat hydatic disease. The aim of this retrospective study is to assess the rate of postoperative complications, mortality rate, hospitalization period, and recurrence for capsulorrhaphy method, and to compare it with other hydatic cyst management techniques. Material and methods. An open surgical procedure using capsulorrhaphy technique was performed on 250 patients (130 men and 120 women) with uncomplicated hydatic cysts in the Northwest of Iran, between 1989 and 2011. Results. The patients stayed in the hospital between 4 and 10 days, with an average of 5 days. Of the patients, 233 (93.2%) were discharged without any complications, 9 (3.6%) developed a wound infection in the abdominal wall, and 7 (2.8%) developed pulmonary atelectasis. Those who developed an infection or an atelectasis stayed in the hospital for few more days for conservative treatments. One of the patients (0.4%) had external biliary fistula and bile leak, which was treated with surgery and Roux-en-Y cystojejunostomy. During follow-ups (13.2 ± 8.5 months), incisional hernias occurred in 5 (2%) patients and hydatid cyst recurrence affected 7 (2.8) patients. The mortality rate was zero amongst the studied patients. Conclusion. Compared to other techniques in the literature, the results presented in the current work indicate that capsulor-rhaphy is an efficient method in terms of decreased postoperative complications, recurrence, and hospitalization period, and is a safe method with low morbidity and zero mortality rates.

  • Association between serum IgE level and adverse clinical endpoints in primary sclerosing cholangitis James H. Tabibian, Felicity Enders, Mohamad H. Imam, Gururaj Kolar, Keith D. Lindor, Jayant A. Talwalkar Page 384-389

    Introduction. Primary sclerosing cholangitis (PSC) is an idiopathic hepatobiliary disorder associated with an increased risk for cholangiocarcinoma (CCA) and a median survival time of 12 years. Reliable predictors of CCA and other major adverse events in PSC are currently lacking. Recently, serum IgE was found to be associated with CCA in a Japanese cohort of PSC patients. Our aim in this study was to determine whether IgE levels predict time to CCA, liver transplantation, or death in a Western (USA-based) cohort of PSC patients. Material and methods. Thirty-eight patients with PSC and IgE levels were identified and categorized into low or high IgE groups based on the sample median. Groups were compared with respect to clinical characteristics and adverse endpoint-free survival, and the association between IgE and endpoints was assessed with multivariate proportional-hazards models. Results. The median sample age at PSC diagnosis was 41 years, and median serum IgE level was 47.6 kU/L. Low and high IgE groups differed significantly only with respect to IgG subclasses, which were higher among the latter (p < 0.05). There were no significant differences in composite endpoint-free (p = 0.83) or CCA-free survival (p = 0.20). In multivariate analyses, only Mayo PSC risk score and MELD score were significant predictors of endpoint-free survival (p < 0.05). Conclusions. Serum IgE level is associated with several IgG subclass levels but not time to CCA, liver transplantation, or death among PSC patients in a USA-based cohort. While Mayo PSC risk score and MELD score can predict these outcomes, more specific predictors of CCA are needed.

  • Akin criteria as a predictor of mortality in cirrhotic patients after spontaneous bacterial peritonitis Alexandre de Araujo, Mario Reis Alvares-da-Silva Page 390-395

    Background and aims. Spontaneous bacterial peritonitis (SBP) often triggers acute-on-chronic liver failure (ACLF). Acute kidney injury (AKI) is frequent and correlates with higher mortality in such cases. The aim of this study is to evaluate the Acute Kidney Injury Network (AKIN) criteria in the prediction of death in cirrhotic patients after an episode of SBP. Material and methods. Forty-six cirrhotic patients with SBP were included in a cohort study. Renal injury was estimated by AKIN criteria (grades 1, 2 or 3) to examine the association between AKI severity and mortality. Patients were followed-up for a mean of 13.22 months. Kaplan-Meier survival curve and the hazard ratio of mortality by Cox regression model were calculated accordingly to the AKIN criteria. Results. The mean age of the included patients was 56.94 ± 9.49; 29 (63%) were male. Mean MELD score was 19.46 ± 6.16; 78.3% were Child-Pugh C. AKI occurred in 43.5% of patients (8.7, 17.4 and 17.4% respectively for AKIN criteria 1, 2 and 3). Inpatient mortality for AKIN 1, 2 and 3 was 50, 37.5 and 62.5 vs. 3.8% for patients without renal injury (p = 0.002, 0.001 and < 0.001 respectively). Patients with AKIN grades 1, 2 or 3 had no significant differences regarding MELD score (p = 0.893). The hazard ratio and 95% confidence interval of mortality for patients with AKI (AKIN grades 1, 2 and 3 grouped) were 3.41 (1.58-7.36). Conclusions. AKIN criteria are useful to predict mortality in patients with SBP.

IMAGES IN HEPATOLOGY

CASE REPORTS

  • A modified heterotopic auxiliary living donor liver transplantation: report of a case Kefeng Dou, Desheng Wang, Kaishan Tao, Shuqiang Yue, Zhenyu Ti, Zhenshun Song, Lin Li, Yong He, Xiaojuan Hou Page 399-403

    Liver transplantation is regarded as an effective treatment for Wilson’s disease (WD), and recently has been shown to improve not only hepatic but also neurologic manifestations. Conventional auxiliary liver transplantation for WD is orthotopic liver transplantation and heterotopic liver transplantation. But the conventional procedure could not avoid the problem of space, functional competition, hemodynamic variation. Here we report a case of heterotopic auxiliary living-donor liver transplantation (HALDLT) to treat WD. We modified the operation to have a splenectomy, implant graft into the splenic fossa. The patient recovered well after the transplantation and has been symptom-free during a 5-year follow-up. This modified operation is more safe and simple. HALDLT might be an effective treatment for WD patients with splenomegaly.

  • Molecular surveillance of Hepatitis A virus in Argentina: first subgenotype IB detected in a traveler María S. Munné, Nancy R. Altabert, Sara N. Vladimirsky, Maria G. Arribere, Sandra F. Ortali, Carina Sijvarger, Lucio O. Otegui Mares, Sonia S. Soto, Leonardo S. Brajterman, Jorge E. González Page 404-406

    By using molecular surveillance of hepatitis A virus, we characterized for the first time a subgenotype IB imported case in Argentina, a country with universal vaccination since 2005. The case was a crew member of a cruise ship. We consider this a case alert because of its multiple implications.

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