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Current Issue

January March, 2010

Vol. 9 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

  • Acute Liver Failure Murali Pathikonda, Santiago J. Munoz Page 7-14

    Acute liver failure is a rare but often catastrophic illness affecting the liver and multiple organ systems. Patients with acute liver failure require a multidisciplinary approach for adequate management. With improved critical care and the availability of liver transplantation, survival has significantly improved. Hepatic encephalopathy, cerebral edema and infections are the most common complications of acute liver failure. The evaluation requires a diligent search for a specific etiology of the liver failure, since certain causes may respond well to specific pharmacological therapies. Acetaminophen and non-acetaminophen drug-induced hepatotoxicity account for more than 50% of cases of acute liver failure. Assessment of prognosis frequently (at least on a daily basis) by using various prognostic tools, allows the treating team to decide whether or not to proceed with urgent liver transplantation. Artificial liver support devices are still in evaluation and not ready for use in clinical practice. While it is determined whether or not there is sufficient hepatic regeneration, the care of the patient with acute liver failure revolves around managing the dysfunction of multiple extra hepatic systems.

ORIGINAL ARTICLES

Clinical Studies

  • Endoscopic band ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhotic patients with high risk esophageal varices Rosa María Pérez-Ayuso, Sebastián Valderrama, Manuel Espinoza, Antonio Rollán, René Sánchez, Francisco Otarola, Brenda Medina, Arnoldo Riquelme Page 15-22

    Background. Gastroesophageal variceal bleeding is a common complication of portal hypertension. Current guidelines recommend β-blockers for primary prophylaxis. However, evidence suggests that endoscopic variceal ligation (EVL) reduce bleeding episodes. Aims. To compare endoscopic EVL with propranolol (PPL) for primary prophylaxis of variceal bleeding. Methods. We conducted a randomized controlled trial. Over a 9-year period, 75 patients with cirrhosis and high-risk esophageal varices (HREV) were recruited and allocated to EVL (n=39) or PPL (n=36). Primary outcome was variceal bleeding. Secondary outcomes were survival, source of bleeding and serious adverse events. Analyses were made by intention-to-treat. Results. Baseline characteristics were similar. Medium follow-up was 1647±1096 days. Complete follow-up was achieved in 85% of patients. Variceal bleeding occurred in 12% of EVL and in 25% of PPL group (p=0.17). The actuarial risks of bleeding after 2 years were similar in both groups. Overall mortality was 51% in EVL and 33% in PPL group (p=0.17). Patients in the EVL group showed a lower rate of esophageal variceal bleeding (5.1% v/s 25%, p=0.027) and a higher rate of subcardial variceal bleeding compared with PPL group (7.7% v/s 0%, p=0.027). Serious adverse events related to EVL occurred in 2 patients, including 1 death. Conclusions. The present study supports that PPL should be considered the first choice in primary prophylaxis of variceal bleeding offering similar effects and lower severe adverse events compared with EVL.

  • Multimodal therapy for hepatocellular carcinoma: A complementary approach to liver transplantation P. Andrew Schumacher, James J. Powell, Andrea J. MacNeill, Andrzej K. Buczkowski, Siegfried R. Erb, Stephen G. Ho, Charles H. Scudamore, Urs P. Steinbrecher, Alan Weiss, Eric Yoshida, Stephen W. Chung Page 23-32

    Objective. To evaluate the survival benefit of multimodal therapy for the treatment of HCC. Background. Orthotopic liver transplantation (OLT) is considered the treatment of choice for selected patients with hepatocellular carcinoma (HCC). However, donor organ shortages and patients whose HCCs exceed OLT criteria require consideration of alternate therapeutic options such as hepatic resection, radiofrequency ablation (RFA), ethanol injection (EI), transarterial chemoembolization (TACE), and chemotherapy (CTX). This study was performed to evaluate the survival benefit of multimodal therapy for treatment of HCC as complementary therapy to OLT. Methods. A retrospective review was conducted of HCC patients undergoing therapy following multidisciplinary review at our institution from 1996 – 2006 with a minimum of a 2 year patient follow-up. Data were available on 247/252 patients evaluated. Relevant factors at time of diagnosis included symptoms, hepatitis B (HBV) and C (HCV) status, antiviral therapy, Child-Pugh classification, portal vein patency, and TNM staging. Patients underwent primary treatment by hepatic resection, RFA, EI, TACE, CTX, or were observed (best medical management). Patients with persistent or recurrent disease following initial therapy were assessed for salvage therapy. Survival curves and pairwise multiple comparisons were calculated using standard statistical methods. Results. Mean overall survival was 76.8 months. Pairwise comparisons revealed significant mean survival benefits with hepatic resection (93.2 months), RFA (66.2 months), and EI (81.1 months), compared with TACE (47.4 months), CTX (24.9 months), or observation (31.4 months). Shorter survival was associated with symptoms, portal vein thrombus, or Child-Pugh class B or C. HCV infection was associated with significantly shorter survival compared with HBV infection. Antiviral therapy was associated with significantly improved survival in chronic HBV and HCV patients only with earlier stage disease. Conclusion. Multimodal therapy is effective therapy for HCC and may be used as complementary treatment to OLT.

  • Distribution of HCV genotypes and HCV RNA viral load in different regions of Mexico Ricardo Jimenez Mendez, Felipe Uribe-Salas, Paulo López-Guillen, Laura Cisneros-Garza, Gilberto Castañeda Hernandez Page 33-39

    Background and aim. To identify the geographic distribution of hepatitis C virus (HCV) genotypes and HCV RNA viral load in a large number of HCV-infected carriers in Mexico. Methods. Patients with chronic hepatitis C (n = 8,802) were studied to identify HCV genotype using an immune line probe assay in samples shown previously to be positive for viral RNA by an RT-PCR test. Baseline HCV RNA was also evaluated. Results. Genotype 1 accounted for 70.3%, genotype 2 for 21.8%, genotype 3 for 7.2%, genotype 4 for 0.3%, and genotype 5 for 0.1% of all cases; coinfection was present in 0.3%. Overall, Genotype 1 was the most prevalent Genotype. Regionally, genotype 1 occurred more frequently in the North-East, North, and Center- East regions of Mexico; genotype 2 was more prevalent in the South, East, and Peninsula regions; and genotype 3 was more prevalent in the North and North-West regions. Only 22.4% of patients with genotype 1 were classified in the low HCV RNA viral load category, and the distribution of this genotype did not differ significantly between regions. Conclusion. The prevalence of HCV genotypes and viral load in Mexico was 70.3% for genotype 1, but only 22.4% of these patients had a low HCV viral load. Distribution was not uniform in Mexico, with greater frequency of genotype 2 in South, East and Peninsula Regions and Genotype 3 in North and North-West Regions.

  • Effects of TIPS on global end-diastolic volume and cardiac output and renal resistive index in ICU patients with advanced alcoholic cirrhosis Andreas Umgelter, Wolfgang Reindl, Fabian Geisler, Bernd Saugel, Wolfgang Huber, Hermann Berger, Roland M. Schmid Page 40-45

    The transjugular porto-systemic stent-shunt (TIPS) reduces portal pressure in cirrhotic patients and is used as a nonsurgical treatment for refractory ascites, recurrent variceal hemorrhage or hepatorenal syndrome. There are concerns regarding a negative impact on cirrhotic cardiomyopathy and deterioration of hyperkinetic circulatory dysfunction. We analyzed a prospectively maintained database containing hemodynamic data on cirrhotic ICU patients. Hemodynamic monitoring was performed using transpulmonary thermodilution (PiCCO, Pulsion Medical Systems, Munich, Germany). Renal perfusion was assessed by Doppler ultrasound during studies of portal and TIPS perfusion before and after the procedure. Complete data sets of 8 patients (4 male, 4 female, age 60 years (52-67), Child-Pugh-Turcotte score 10 (8-12)) were available. After TIPS, there was a substantial increase of GEDVI (646 ml/m2 (580-737) to 663 mL/m2 (643-792); p=0.036) that was even more pronounced at 24 hours (716 mL/m2 (663-821); P=0.012). CI increased from 3.3 L/min/m2 (3.1-4.2) to 3.9 L/min/m2 (3.6-5.3) (p=0.012) and 3.9 L/min/m2 (3.7-5.2) (p=0.017), respectively. There was a significant decrease of renal RI from 0.810 (0.781-0.864) to 0.746 (0.710-0.798) (p=0.028) and a transient increase of fractional excretion of sodium. SVRI (1737 dyn*s/cm5/m2 (1088 – 2115) vs. 1917 dyn*s/cm5/m2 (1368-2177) was not significantly altered immediately after TIPS but decreased to 1495 dyn*s/cm5/m2 (833- 1765) at 24 hours (p=0.036)). There were no significant changes of mean arterial pressure (MAP). In conclusion, TIPS resulted in a pronounced increase of central blood volume. The observed hemodynamic effects are compatible with a preload driven increase of cardiac output and secondary decreases in SVRI and RI.

  • Efficacy, tolerability and safety in the treatment of chronic hepatitis C with combination of PEG - Interferon - Ribavirin in daily practice Ezequiel Ridruejo, Raúl Adrover, Daniel Cocozzella, Nora Fernández, María Virginia Reggiardo Page 46-51

    Background. Efficacy and safety of Pegylated Interferon alfa (PegIFN)-Ribavirin (RBV) for the treatment of chronic hepatitis C (CHC) in routine clinical practice seems to be comparable with results of randomizedcontrolled trials. Aims. To evaluate the efficacy, tolerability and safety of CHC treatment with PegIFN + RBV in "real world" patients in Argentina and to analyze factors associated with SVR. Methods. Medical records of patients treated according to current guidelines from 2001 to 2008 were reviewed. Results. 235 patients were included and 80.8% completed treatment. Discontinuation occurred in 7.6% due to adverse events (AE), and 1.2% dropped-out treatment. Overall SVR was 60.8%. Multivariate analysis demonstrated that being naive (p 0.031) and low basal viral load (p 0.006) were associated with SVR, whereas F3-F4 (p 0.001) and elevated ALT (p 0.023) were associated with non-response. 80% of planned doses completed was associated with 74% SVR (p <0.001). At least one AE was reported in 93.6% of the patients: neutropenia in 27.6%, thrombocytopenia in 15.3%, anemia in 38.7%, psychiatric symptoms in 63.4%, thyroid dysfunction in 10.2%. Conclusion. Efficacy, tolerability and safety of treatment of CHC in daily practice in Argentina are similar to those reported in randomized controlled trials.

  • High ghrelin and obestatin levels and low risk of developing fatty liver Ylse Gutierrez Grobe, Israel Villalobos-Blasquez, Karla Sánchez-Lara, Antonio R. Villa, Guadalupe Ponciano-Rodríguez, Martha H. Ramos, Norberto C. Chávez Tapia, Misael Uribe, Nahum Méndez-Sánchez Page 52-57

    Aim. Obesity and insulin resistance are associated with nonalcoholic fatty liver disease (NAFLD). It was recently reported that the ratio between levels of ghrelin and obestatin is also associated with obesity and insulin resistance. We investigated the association between the ghrelin/obestatin ratio and NAFLD. Methods. This cross-sectional study included 98 subjects (51 NAFLD patients and 47 controls). Anthropometric, metabolic and biochemical variables were measured and serum concentrations of ghrelin and obestatin were determined. Logistic regression analyses (univariate and multivariate) were conducted to determine whether NAFLD was associated with ghrelin and obestatin levels and the ghrelin/obestatin ratio. Results. We studied 51 NAFLD cases and 47 controls. Men comprised 82% of cases and 61% of controls. The mean ages of the groups differed significantly. Body mass index (P < 0.001), waist circumference (P < 0.001) and WHR (P < 0.001) were significantly greater in the NAFLD group than in the control group. The NAFLD group had higher mean fasting glucose level (P = 0.001), HOMA-IR index (P < 0.001) and triglyceride level (P < 0.001) than the controls. Ghrelin and obestatin concentrations were classed according to tertiles. Multivariate analysis revealed a negative correlation between ghrelin and obestatin levels and an overweight status, obesity and metabolic syndrome. Ghrelin and obestatin were evaluated in multivariate logistic regression analysis, they had a protective effect against hepatic steatosis after controlling for potential confounders. Conclusion. Serum ghrelin and obestatin concentrations are correlated with a low risk of developing NAFLD. However, ghrelin/obestatin ratio was not correlated with NAFLD.

  • Serum cystatin C measurement in differential diagnosis of intra and extrahepatic cholestatic diseases Mehmet Buyukberber, Irfan Koruk, Oztekin Cikman, Mehmet Koruk, Mehmet Emin Küçükoglu, Abdullah Sakman, Omer Demir, Saime Sahinoz Page 58-62

    Objective. Cystatin C is a very potent inhibitor of cysteine proteinases and, it has been clinically applied as a sensitive marker in monitoring of renal and liver functions. The aim of this study was to reveal whether cystatin C may be a useful marker for distinguishing intra- versus extrahepatic cholestasis. Materials and methods. Serum cystatin C concentrations were determined by nephelometric immunoassay using N latex cystatin C kit in 53 patients with cholestatic disorder that included 18 patients with intrahepatic cholestasis , 17 patients with malignant extrahepatic cholestasis , 18 patients with benign extrahepatic cholestasis. Serum cystatin C concentration was also determined in 20 healthy volunteers. Results. Mean serum cystatin C concentration was 2.82 ± 0.24 mg/l (SD) in patients with intrahepatic cholestasis, 2.05 ± 0.15 mg/l in patients with extrahepatic malignant cholestasis, 1.37 ± 0.13 mg/l in extrahepatic benign cholestatic patients and 0.93 ± 0.24 mg/l in control group. Serum cystatin C concentrations in patients with cholestatic disease were significantly higher than those in the healthy controls (p < 0.001). Moreover, mean serum cystatin C concentration in patients with intrahepatic cholestasis was higher than those in extrahepatic cholestasis groups (p < 0.001). Serum cystatin C concentrations were significantly higher in patients with malignant extrahepatic cholestasis than in patients with benign extrahepatic cholestasis (p < 0.001). There were no correlations patients among serum cystatin C concentrations and serum levels of AST, ALT, ALP, GGT, total and conjugated bilirubin. Conclusion. Our results suggested that serum cystatin C level may be a potential biochemical marker both to point out an intrahepatic origin by excluding an extrahepatic source of cholestasis in patients with jaundice and to possibly differentiate bening and malignant extrahepatic cholestatic disorders.

  • Etiology of hepatocellular carcinoma in Latin America: a prospective, multicenter, international study Eduardo Fassio, Solangel Díaz, Catalina Santa, María Elisa Reig, Yamila Martínez Artola, Angelo Alves de Mattos, Carlos Míguez, Joao Galizzi, Rodrigo Zapata, Ezequiel Ridruejo, Francisco Carlos de Souza, Nelia Hernández, Leonardo Pinchuk Page 63-69

    Background/aims. No prospective study has been published investigating etiology of HCC in Latin America. The primary aim of this prospective study was to analyze the etiology of liver disease in patients with HCC from our area. Secondary aims were to evaluate staging using Okuda and BCLC classifications; and percentage of patients receiving treatment. Methods. The Governing Board of the Latin American Association for the Study of the Liver designed the protocol. During a 18 month period, all members were invited to load their incident HCC cases on line. Results. 240 cases from 9 countries were uploaded, 174 were male (72.5%), median age was 64 years, interquartile range 57-72. In 85.4% of cases, patients had underlying cirrhosis. Main etiological factors were: HCV in 74 patients (30.8%), alcohol in 49 (20.4%), cryptogenic cirrhosis in 35 (14.6%), HBV in 26 (10.8%), HCV plus alcohol in 14 (5.8%). Considering the combinations, hepatitis C was shown in 91 patients (38%); chronic alcoholism in 68 patients (28%); and hepatitis B in 33 patients (14%). There were no significant differences between the groups in the age at diagnosis. Percentage of male gender was higher in groups of alcohol (94%), HCV plus alcohol (93%) and HBV (85%) than in cryptogenic cirrhosis (60%) and HCV (59%) (p<0.001). Conclusions. Our prospective study showed that hepatitis C is the more frequent etiology of HCC in Latin America, followed by alcoholic cirrhosis. Demographical results showed a male predominance (male:female ratio 2.6) with an important proportion of patients being diagnosed at their sixties.

  • Hepatotoxicity due to rifampicin, isoniazid and pyrazinamide in patients with tuberculosis: Is anti-HCV a risk factor? Lysandro Alsina Nader, Angelo Alves de Mattos, Pedro Dornelles Picon, Sérgio Luis Bassanesi, Angelo Zambam De Mattos, Margarita Pineiro Rodriguez Page 70-74

    Background and Rationale. Among the adverse events related to tuberculosis treatment, hepatotoxicity is the most serious, and recognition of risk factors for it is essential to achieve successful therapy. The aim of the study is to evaluate the role of anti-HCV as a risk factor for hepatotoxicity in hospitalized patients under tuberculosis treatment with rifampicin, isoniazid and pyrazinamide (RHZ). Methods. Historical cohort study carried out at Hospital Sanatório Partenon, from 1998 to 2006. Patients aged 18 years or older, tested for anti-HCV, who presented normal pre-treatment aminotransferases (AST, ALT) and bilirrubin and who used RHZ during hospitalization were included in the study. Individuals who used anti-tuberculosis drugs six months prior to hospitalization, had clinical evidence of chronic liver disease or showed previous history of hepatotoxicity to RHZ were excluded. Results. A sample of 534 patients was studied. The incidence of hepatotoxicity was 8.8% (n = 47). After univariate analysis, the following variables were associated to hepatotoxicity: anti-HIV positive, anti-HCV positive, use of antiretroviral therapy and high doses of rifampicin and isoniazid per kg of body weight (p < 0.05). When Cox regression was performed, anti-HIV positive [RR = 2.3 (IC95% 1.2-4.1); p = 0.008] and high doses of isoniazid per kg of body weight [RR = 1.3 (IC95% 1.1-1.7); p = 0.016] remained independently associated to development of hepatotoxicity. Conclusions. In conclusion, the anti-HIV positive and high doses of isoniazid were considered independent risk factors for hepatotoxicity due to RHZ esqueme in the present study. Though univariate analysis showed that anti-HCV was associated to the outcome, it was not identified as an independent risk factor for hepatotoxicity related to the use of RHZ when the analysis was controlled to HIV.

  • Hepatoblastoma. Clinical experience at a single institution using the Siopel staging system Carlos A. Leal-Leal, Victoria Imaz-Olguín, Julieta Robles-Castro, Jaime Shalkow-Klincovstein, José M. Palacios-Acosta Page 75-79

    Background. Staging in Hepatoblastoma has recently become controversial. In developing countries diagnosis occurs mostly in advanced stages under these circumstances, we propose another option that can be considered of prognostic value. Method. A retrospective analysis of cases diagnosed with Hepatoblastoma (HB), treated in a single Institution, in nine years was conducted. Chemotherapeutic regimens were analyzed, as well as the number of courses administered and response to treatment. Results. Thirty-two patients were studied. Patients had symptoms from 1 to 25 weeks before diagnosis. SIOP stratification was used, finding 12 cases in PRETEXT II, 6 cases in PRETEXT III, and 14 cases in PRETEXT IV. No single case was identified in PRETEXT I. Conclusions. When comparing survival using the PRETEXT system, SIOP and our study showed marked differences. These results may not be comparable due to differences in tumor volume among the same PRETEXT stratification. We believe that tumor volume is related to prognosis.

ORIGINAL ARTICLES

Basic studies

  • Methimazole-induced hypothyroidism causes alteration of the REDOX environment, oxidative stress, and hepatic damage; events not caused by hypothyroidism itself Edgar Cano-Europa, Vanessa Blas-Valdivia, Gabriel Eduardo Lopez-Galindo, Margarita Franco-Colin, Marisol Pineda-Reynoso, Adelaida Hernandez-Garcia, Rocio Ortiz-Butron Page 80-88

    Our objective was to compare, over a time-course, markers of oxidative stress, the REDOX environment, and the antioxidant enzymatic system in the liver of rats with methimazole- or thyroidectomy-caused hypothyroidism. Methods. We used 60 male Wistar rats divided into four groups: 1) the euthyroid, which received only tap water, 2) false thyroidectomy, which received the surgery and postoperative treatment, 3) thyroidectomy-caused hypothyroidism, which had the thyroid gland removed and a parathyroid reimplant, and 4) methimazole-caused hypothyroidism in rats that received 60 mg/kg/d of the antithyroid drug in drinking water. Five rats of the euthyroid and methimazole-caused hypothyroidism groups were killed at the end of the first, second, third, and fourth week after treatment, and five rats of false thyroidectomy and thyroidectomy-caused hypothyroidism groups were killed at the end of the second and eighth week after the surgical procedure. Each liver was removed and stored at -70 °C until oxidative stress, REDOX environment, and antioxidant enzymatic system markers were tested. We also made a histological study at the end of the treatment. Results. The histological study revealed that only the methimazole-caused hypothyroidism caused cell damage. This damage is associated with an increase of oxidative stress markers that were not compensated for by the antioxidant system. The catalase activity is reduced and this allows H2O2-caused damage. In conclusion methimazole causes cell damage in the liver, whereas hypothyroidism per se does not cause hepatic-cell damage.

EDITORIAL

IMAGES IN HEPATOLOGY

CASE REPORTS

  • Actinomycotic liver abscess: A rare complication of colonic diverticular disease Vijay Joshi, Anastasios Koulaouzidis, Steve McGoldrick, Mark Tighe, Chew Tan Page 96-98

    We present the first case of hepatic actinomycosis requiring both medical and surgical intervention due to liver dissemination from a primary colonic abscess. A 52-year-old white male had a computerised (CT) abdominal scan following an episode of collapse and was found to have peri-colonic and hepatic abscesses. Prior to this episode, he suffered with a two month history of fever, unexplained weight loss, and anaemia suggesting possible malignancy. He was treated with both radiological and surgical drainage of the abscesses, alongside the antibiotic cover and underwent an anterior colonic resection with primary anastomosis. There have been no previous reports of an actinomycotic liver abscess complicating colonic diverticular abscess. A multi- team approach is recommended when disseminated actinomycotic infection is encountered.

  • Endovascular treatment of a hepatic artery aneurysm causing chronic abdominal pain; a case report Gabrielle L. de Ruiter-Derksen, Rutger CG Bruijnen, Frank Joosten, Michel MP J Reijnen Page 104-106

    Background. Aneurysms of the visceral arteries are rare but potentially lethal lesions. We describe a case of a successful endovascular exclusion of a hepatic artery aneurysm in a patient that suffered from chronic abdominal pain. Case Report. A 68-year old man presented with chronic abdominal pain that had existed for 10 months. A diagnostic contrast-enhanced CT scan showed an 18 mm atherosclerotic aneurysm of the hepatic artery. When other pathology was excluded the aneurysm was excluded using an ePTFE-covered nitinol stent graft. Post-deployment angiograms showed a complete exclusion of the aneurysm. The abdominal complaints immediately resolved. After a follow-up period of 18 months patient had a patent endograft and remained free of symptoms. Conclusions. Small hepatic artery aneurysms may cause chronic recurrent abdominal pain and can be safely excluded using a covered stent graft.

  • Liver involvement in severe human influenzaAH1N1 Raúl Carrillo-Esper, Estela Pérez Bustos, Sofía Ornelas-Arroyo, Jorge Albores-Saavedra, Misael Uribe Page 107-111

    Influenza A is a disease caused by a RNA virus, member of the orthomyxoviridae family. The influenza infection is characterized primarily by pulmonary affection that may advance to an acute pulmonary respiratory failure course. Hepatic involvement is not frequent and accounts for < 3% of all cases. We describe two patients with acute Influenza A H1N1 infection who developed hepatic involvement. Needle core liver biopsy of one of the patients revealed only micro and macrovesicular steatosis.

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